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Probing the Hydrogen-Bonding Environment of Individual Bases in DNA Duplexes with Isotope-Edited Infrared Spectroscopy
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B: Biophysical and Biochemical Systems and Processes

Probing the Hydrogen-Bonding Environment of Individual Bases in DNA Duplexes with Isotope-Edited Infrared Spectroscopy
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  • Robert J. Fick
    Robert J. Fick
    Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States
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  • Amy Y. Liu
    Amy Y. Liu
    Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
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  • Felix Nussbaumer
    Felix Nussbaumer
    Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria
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  • Christoph Kreutz
    Christoph Kreutz
    Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria
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    Orcidhttps://orcid.org/0000-0002-7018-9326
  • Atul Rangadurai
    Atul Rangadurai
    Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
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  • Yu Xu
    Yu Xu
    Department of Chemistry, Duke University, Durham, North Carolina 27710, United States
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  • Roger D. Sommer
    Roger D. Sommer
    Molecular Education, Technology, and Research Innovation Center, North Carolina State University, Raleigh, North Carolina 27695, United States
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    Orcidhttps://orcid.org/0000-0003-1422-5967
  • Honglue Shi
    Honglue Shi
    Department of Chemistry, Duke University, Durham, North Carolina 27710, United States
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    Orcidhttps://orcid.org/0000-0003-3847-1652
  • Steve Scheiner
    Steve Scheiner
    Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322, United States
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    Orcidhttps://orcid.org/0000-0003-0793-0369
  • Allison L. Stelling*
    Allison L. Stelling
    Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States
    Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
    *Email: [email protected]. Tel: (972) 883-6718.
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    Orcidhttps://orcid.org/0000-0002-0368-0852
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The Journal of Physical Chemistry B

Cite this: J. Phys. Chem. B 2021, 125, 28, 7613–7627
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https://doi.org/10.1021/acs.jpcb.1c01351
Published July 8, 2021

Copyright © 2021 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Measuring the strength of the hydrogen bonds between DNA base pairs is of vital importance for understanding how our genetic code is physically accessed and recognized in cells, particularly during replication and transcription. Therefore, it is important to develop probes for these key hydrogen bonds (H-bonds) that dictate events critical to cellular function, such as the localized melting of DNA. The vibrations of carbonyl bonds are well-known probes of their H-bonding environment, and their signals can be observed with infrared (IR) spectroscopy. Yet, pinpointing a single bond of interest in the complex IR spectrum of DNA is challenging due to the large number of carbonyl signals that overlap with each other. Here, we develop a method using isotope editing and infrared (IR) spectroscopy to isolate IR signals from the thymine (T) C2═O carbonyl. We use solvatochromatic studies to show that the TC2═O signal’s position in the IR spectrum is sensitive to the H-bonding capacity of the solvent. Our results indicate that C2═O of a single T base within DNA duplexes experiences weak H-bonding interactions. This finding is consistent with the existence of a third, noncanonical CH···O H-bond between adenine and thymine in both Watson–Crick and Hoogsteen base pairs in DNA.

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1. Introduction

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Determining the hydrogen bonding (H-bonding) status of individual bonds in nucleic acids is key to understanding their structure, dynamics, and biological functions. This includes recognition by proteins, localized melting required for transcription and replication of DNA, and determining how specific sequences can be targeted with drugs. H-bonds are also critical for determining the complex tertiary structures formed by RNA. Understanding how key H-bonding interactions impact the three-dimensional structure of DNA is essential for determining how our chemical code is recognized by cellular machinery on a molecular level. This knowledge is critical for unraveling processes key to vitality, including replication and transcription, particularly, as it is the dysregulation of these processes that drives genetic diseases such as cancer. Yet, measuring the strength of individual hydrogen bonds (H-bonds) in DNA duplexes between the adenine (A)–thymine (T) and guanine–cytosine base pairs proposed by Watson and Crick (1) (Figure 1A) in the 1950s remains a challenge, particularly in the native solution environment.

Figure 1

Figure 1. CH···O H-bonding in A–T DNA base pairs. (A) Potential, third CH···O H-bond in Watson–Crick and (B) Hoogsteen A–T DNA base pairs. (C) Typically used geometric definition for CH···O H-bonds.

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While the Protein Data Bank (PDB) contains thousands of DNA and DNA/protein structures at angstrom-level resolution, these structures can be profoundly impacted by the crystal packing. For example, there are a number of AT-rich DNA duplexes that crystallize as all-Hoogsteen base pairs (2,3) rather than the canonical Watson–Crick pairs. In Hoogsteen base pairs (4,5) (Figure 1B), the A or G base is flipped 180° from its anti configuration to syn, forming a completely new set of H-bonds with the T or C and exposing the Watson–Crick face of the purine base. However, many of these all-Hoogsteen duplexes are in fact Watson–Crick when examined in solution NMR, (6) highlighting a need for methods sensitive to the molecular structure of individual DNA bases that can be performed in the native aqueous environment.
Two of the predominantly used molecularly resolved methods for detecting H-bonding in solution are NMR and vibrational spectroscopies. While NMR is exquisitely sensitive to the structure and electrostatic environment of individual bases, size limitations and chemical exchange render detection and measurement of H-bonds in large DNA/protein complexes challenging. Infrared (IR) spectroscopy is one of the few solution-state methods sensitive enough to changes in H-bonding and molecular structure that it can, for example, distinguish between Watson–Crick and Hoogsteen base pairs, even in large DNA/protein complexes. (7) The frequencies of carbonyl stretching vibrations in particular are well-known (8−11) to change when in strong vs weak H-bonds. C═O stretches can serve as sensitive probes for their immediate electrostatic environment (12−14) and tend to have strong IR intensities that fall in a spectral window clear of signals due to the other molecular bonds. Carbonyl stretches have a long history of use for probing important H-bonding interactions in biological systems using vibrational spectroscopy, particularly as changes in C═O positions can be directly related to the enthalpy of H-bond formation, (10,15−18) provided suitable calibrations are performed. For example, the C═O bond of S-acetyl-CoA was used as a probe to measure the degree of H-bonding to the acyl group when the cofactor was bound to α-chymotrypsin. (16)
DNA has been extensively studied by both one- (19−22) and two-dimensional (23−28) IR spectroscopy to probe the ground states and time-resolved methods (29−31) to probe excited electronic states. However, three out of four of the bases contain at least one C═O bond, resulting in a highly overlapped region between 1600 and 1700 cm–1 in nucleic acid IR spectra. This renders detection of a particular C═O signal from any single base for use as a molecular probe of the base’s local electrostatic environment quite challenging. Here, we overcome this challenge using site-specifically incorporated, isotopically labeled bases and spectral subtraction to dramatically reduce spectral overlap. Isotope labeling is a well-established method for assigning signals to vibrations from particular atomic groups in congested IR and Raman spectra of polyatomic molecules. A multitude of studies have incorporated 13C═O or 13C═18O labels into the amide backbone of proteins (32,33) and peptides, (34−38) or of small-molecule enzymatic substrates, (15,39,40) to analyze the hydrogen bonding status of these groups. A recent study used fully 15N- and 13C-labeled DNA bases to examine coupling in G-quadruplexes with ultrafast 2DIR spectroscopy. (41)
A specific application that exploits isotope labeling is isotope editing experiments in which the IR (or Raman) spectrum of the heavy isotope is subtracted from its light counterpart (see the schematic in Figure 2A), canceling out overlapping signals from modes due to other bonds in the molecule. It is more straightforward to ascribe the resulting difference signals to specific functional groups in large molecules, particularly those vibrations which are well-localized to two or three atoms. In nucleic acids, previous studies examined the conformation of adenine bases within DNA duplexes (42) and DNA/protein complexes (43) using deuterium-labeled adenine bases. More recent studies employed isotope editing experiments using commercially available, fully 15N- and 13C-labeled RNA bases to track incorporation of a single labeled base using Raman microscopy during an RNA polymerase reaction. (44−46) However, to the best of our knowledge, to date, no isotope editing studies have been performed that label an individual C═O in nucleic acids.

Figure 2

Figure 2. Isotope editing and spectral subtraction isolate isotope signals from individual T bases in DNA duplexes. (A) In isotope editing experiments, an isotopically labeled base is site-specifically incorporated into a DNA duplex (heavy, blue) and the heavy IR spectrum is subtracted from the IR spectrum of a light duplex (black), which has an identical sequence. In the “light–heavy” subtraction spectrum, signals due to the light 12C═O appear as positive bands, and signals due to the heavy 13C═O appear as negative bands. Signals that arise from vibrations in which the C2 atom does not participate are canceled out, thus reducing spectral congestion so that C═O stretching of a specific bond of an individual DNA base can be observed in the duplex environment. (B) B-form DNA duplex illustrating the local environment of a TC2═O bond. Arrows indicate nearby functional groups on neighboring bases that may impact the stretching frequency. Distances are in angstrom.

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Here, we develop an IR-based isotope editing method to report the first detection of the TC2═O frequency in individual DNA bases when in duplexes containing two different types of A–T base pairs: Watson–Crick (1) and Hoogsteen. (5,47) For these initial experiments, we focused on the C2 atom of T as the C2═O stretch as, based on earlier (48) and more recent (28,49) experimental studies, we expected it to be localized to the C and O atoms, making it a suitable reporter for its immediate chemical environment. The TC2═O bond is located in the minor groove of B-form DNA (Figure 2B) and is therefore expected to be sensitive to interactions with adenine C2–H, any solvent waters or ions that may bind to the minor groove, and stacking interactions from the adjacent bases immediately above or below it.
Here, we present the “light minus heavy” isotope subtraction spectra (Figure 2A) for a series of DNA duplexes, each 12 base pairs in length. These specific sequences were chosen for two main reasons. First, they have been extensively examined with solution NMR methods and, second, two out of the three sequences can form A–T Hoogsteen base pairs when either bound to a drug (echinomycin) or when chemically modified to enforce Hoogsteen pairing, thus allowing us to determine if the stretching is sensitive to changes in the sequence context, in base pairing, and in the minor groove environment. Our third sequence serves as a control for the drug-bound A–T Hoogsteen base pairs as this sequence binds to the drug but maintains Watson–Crick A–T base pairing when bound. Thus, this initial series of duplexes allows us to test the sensitivity of the C2═O bond to two different types of base pairing, Watson–Crick and Hoogsteen, in systems that have been validated to form each under solution conditions by NMR spectroscopy.
We compare the position of the TC2═O stretching frequency in these DNA duplexes to that from the thymine base in solvents with different H-bonding capacities. Collectively, our results indicate that TC2═O in DNA duplexes experiences a weak H-bonding interaction. This may be due to the presence of a weak CH···O H-bond (Figure 1C) in A–T Watson–Crick and Hoogsteen DNA base pairs, which is suggested to exist in computational studies (50,51) but has been vigorously disputed. (52−54) Alternatively, the interaction may arise due to a weakly bound water molecule in the minor groove of the DNA duplexes, which has been observed in crystal structures, (55−63) solution NMR (64,65) and 2DIR (66−69) studies, and molecular dynamics caluclations. (70,71)
Our results are a powerful proof of concept of how isotope editing with labeled DNA bases is a robust, solution-state detection method capable of pinpointing individual chemical bonds encased in very large macromolecular complexes. As carbonyls are present in every nucleic acid save for adenine, we anticipate that this method can be applied to study the electrostatic environment of individual bases in a broad range of DNA- and RNA-containing systems, including their complexes with drugs and proteins.

2. Materials and Methods

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2.1. Chemicals

Unless otherwise indicated, all chemicals for buffers, thymine base small-molecule mimics, echinomycin, and solvents were purchased from Sigma-Aldrich. Natural-abundance DNA duplexes were purchased from Integrated DNA Technologies. Fully labeled TA-DNA was purchased from Yale-Keck.

2.2. Synthesis of 13C2 -Labeled Thymine Phosphoramidite

Scheme 1 shows the chemical structure of the synthetic intermediates and an overview of the route. See the Supporting Information Methods section for experimental details, yields, and spectroscopic characterization for compounds 1–6.

Scheme 1

Scheme 1. Synthesis of 2-13C-Labeled Thymidine Phosphoramiditea
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a(a) Acetic anhydride, 90 °C, 1 h, and 81%; (b) Pd/BaSO4 5%, H2, in AcOH/H2O, 16 h, rt, and 67%; (c) 1. HMDS, TMS-Cl, 120 °C, 16 h, then Hoffer′s α-chlorosugar, in CHCl3, 4 h, 40 °C, and 56%; (d) CH3NH2 in EtOH 8 M, 16 h, RT, and 88%; (e) DMT-Cl, DMAP, in pyridine, 3 h, rt, and 71%; and (f) CEP-Cl, DIPEA, in CH2Cl2, RT, 3 h, and 74%. DMT, 4,4′-dimethoxytrityl and CEP, 3′-O-(N,N-diisopropyl phosphoramidite).

2.3. IR Experiments

2.3.1. General

All DNA IR measurements were performed at DNA concentrations between 5 and 10 mM in a sodium phosphate buffer (25 mM sodium phosphate, 15 mM NaCl) at pH 6.9. IR measurements were performed with a PerkinElmer Frontier FTIR spectrometer using an NB MCT detector, a PIKE MIRacle diamond ATR attachment, and a CaF2 coverslip as previously described. (7,72) In general, 128 scans at 4 cm–1 resolution were taken for each measurement and the average of minimum three measurements was used for averaging in OriginPro. All DNA duplex spectra were baselined with the Spectrum multipoint baselining function and normalized to the phosphate band at ∼1080 cm–1. Isotope editing subtractions were performed in the Spectrum (PerkinElmer) software using the subtraction function and the average of at least three independent replicates was exported and used for averaging in OriginPro.

2.3.2. Oligonucleotide Synthesis

Single strands containing the T 13C2 isotope were synthesized on a MerMade synthesizer using standard protocols. (73) The 13C thymine C2-labeled single strands were synthesized in-house using a MerMade 6 Oligo synthesizer. 13C C2-labeled thymine phosphoramidites, standard DNA phosphoramidites (n-ibu-G, n-bz-A, n-ac-C, and T Chemgenes), and columns (1000 Å from Bioautomation) were used with a coupling time of 1 min, with the final 5′-dimethoxytrityl (DMT) group retained during synthesis. The oligonucleotides were cleaved from the supports (1 μmol) using ∼1 mL of AMA (1:1 ratio of ammonium hydroxide and methylamine) for 30 min and deprotected at room temperature for 2 h. The single strands were then purified using Glen-Pak DNA cartridges, with ethanol precipitated and resuspended in water for subsequent annealing.
All unlabeled DNA duplexes were annealed as previously described. (72) Briefly, complementary single-stranded DNA were combined in 0.5 mL of ddH2O or buffer, allowed to anneal at 95 °C for ∼5 min, and cooled at ambient temperature for at least 45 min. The samples were then concentrated and exchanged at least three times into the sodium phosphate buffer using 0.5 mL Amicon (Millipore) with a MW cutoff of 10 kDa. All IR measurements used the flowthrough from the previous exchange as the background spectrum.

2.3.3. Echinomycin Binding

Echinomycin reactions with both TA- and AT-DNA duplexes were performed as previously described (74−80) with minor modifications. Echinomycin was dissolved in methanol (∼5 mL methanol per 1 echinomycin) and the concentration was determined via UV–vis spectroscopy using the extinction coefficient at 325 nm (11.5 mM–1 cm–1). (81) A three-fold molar excess of echinomycin was used for binding. To ensure binding, DNA was diluted such that it was at an equal volume with the methanol/echinomycin solution and shaken at room temperature for at least 2 h. The mixture was then divided into 1.5 mL Eppendorf tubes and allowed to slowly air-dry overnight. Once dry, the reaction was resuspended using ddH2O in a volume equal to that of the buffer and concentrated in 0.5 mL Amicon to a volume of ∼30 to 50 μL. This was then exchanged into the sodium phosphate buffer at least three times before measurement with IR. The extent of binding was determined by inspection of the symmetric phosphate stretching band at 1085 cm–1 in the IR spectra of complexes, which shows a characteristic loss of the shoulders at ∼1020 and 1050 cm–1 and gain at ∼1040 cm–1 upon binding. Additional markers for drug binding in the IR include an increase in the intensity in the C═O stretching region at ∼1650 cm–1 and the red shift to the antisymmetric phosphate stretching by ∼6 cm–1.

2.3.4. Solvatochromatic IR Experiments with Thymine Bases

For experiments in water, both dTTP (∼100 mM) and a single-stranded poly-T 12-mer (∼3 mM) were used to determine the C2═O positions. For dimethylformamide and d6-DMSO measurements, 1-methylthymine was used to increase solubility. Briefly, 2–3 mg of 1-methylthymine was dissolved by heating at ∼95 °C for less than 10 min, and 16 scans were used to avoid sample evaporation. The highest frequency C═O signal, which usually lies between 1650 and 1800 cm–1, was then plotted against the solvent acceptor number and a linear regression was performed in Excel.

2.4. Crystallization of 9-Methyladenine and 1-Methylthymine

Crystals of the dimer were grown by combining equal amounts (∼1 mL) of 0.1 M solutions of 9-methyladenine and 1-methylthymine in a 5 dram vial. The volume was reduced by slow evaporation to approximately one-half. The vial was then covered and the cap loosened to allow for further evaporation to 1/4 volume. This process yielded large rod-shaped crystals. Typical crystals had a height and a width of 0.1 and 0.2 mm, respectively, and varied in length from 0.5 to 1.2 mm. A representative crystal (0.096 × 0.212 × 0.572 mm3) was selected and mounted on a 0.1 mm MiTeGen mount.
Diffraction data were collected using a Bruker-Nonius X8 Kappa APEX II diffractometer and Mo Kα radiation (λ = 0.71073 Å) from a fine-focus sealed tube and graphite monochromator. Corrections were applied using SADABS (Bruker-AXS Inc. (2019)), Madison Wisconsin. The structure was solved using direct methods and refined using least-squares refinement of F2 and the SHELXTL software package (Bruker-AXS Inc. (2019), Madison Wisconsin). All nonhydrogen atoms were refined anisotropically. Most H atoms were visible in the difference map in the later stages of refinement but were placed at standard calculated positions. Alkyl and aryl H atoms were allowed to ride on the parent atom position with isotropic displacement parameters set to 1.2 and 1.5 times that of the parent atom, respectively. Positions for hydrogen atoms involved in close contacts of interest for this study were allowed to be refined while maintaining the isotropic displacement parameter restraint.
The dimer crystallizes in space group P21/m. General information is tabulated in Table S1. The molecule sits on the mirror plane. Close contacts between A and T are consistent with those of earlier structures (47,82−84) with negligible variation in intermolecular contacts. For this work, the rotational disorder of the methyl groups was modeled across the mirror plane. Structure determination confirms that the crystals used for this work are indeed consistent with the structure used to analyze the spectroscopic and electronic properties in this study.

2.5. Ab Initio Calculations

Ab initio calculations made use of the MP2 treatment of electron correlation along with the polarized 6-31+G* basis set, within the context of the Gaussian-09 set of codes. (85) Heavy atoms were frozen in their experimentally determined positions, while H atom positions were fully optimized. Interaction energies were evaluated as the difference in energy between each base pair and the energy sum of the individual monomers and then corrected for the basis set superposition error by the standard counterpoise protocol. (86) The densities of the H-bond critical points were evaluated by the AIMALL program. (87)

3. Results

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3.1. Isotope Editing Pinpoints TC2═O Signals from Individual Bases in Large DNA Duplexes and DNA/Drug Complexe

3.1.1. Detection of Watson–Crick TC2═O Signals in Two DNA Duplexes with Isotope Editing

For performing isotope editing experiments, there is a choice between two different T isotopes. The commercially available, fully 13C- and 15N-labeled nucleic acid bases used in previous IR and Raman studies are labeled at every carbon and nitrogen atom, including the sugar and backbone carbons. Isotopically substituting many atoms results in a heavier mass change, which may result in a stronger difference spectrum and thus provide higher contrast in large DNA/protein complexes. However, the difference signal obtained from multiple isotope incorporation may be more complex than that of a duplex containing only one or two labeled atoms due to the multiple mass changes. This mass effect might make ascribing physical interpretations to specific atomic groups, such as an individual C═O bond, very challenging as it would be difficult to determine the extent to which the observed signal is due to a vibration that is localized to the carbonyl of interest. We therefore first sought to compare the difference spectra taken between light and heavy DNA duplexes when using the fully labeled T and a T with only one 13C label inserted at the C2 position, which was chosen as the C2═O stretching vibration is more likely to be localized to the C and O atoms (88) and therefore be a faithful reporter of the H-bonding environment of the minor groove.
We therefore site-specifically installed fully 13C- and 15N-labeled and single-atom 13C2-labeled thymine bases into a TA-DNA duplex (Figure S1). As this sequence is a palindrome (Figure 3A), each duplex now contained two labeled T bases. The spectrum of the unlabeled (light) TA-DNA duplex was subtracted from that of the labeled (heavy) one (Figure S1A) to produce a difference spectrum for each type of label (Figure S1B) in which positive signals are due to the light isotope vibrations, and negative signals from the heavy ones. The difference signal in the fully labeled T is more pronounced but significantly more complex than that of the single-atom 13C- and 15N-labeled T due to the multiple mass changes, rendering any potential physical interpretation of the data challenging. To circumvent this complexity, we decided to develop singly 13C2-labeled T as a probe for the H-bonding environment of A–T base pairs in DNA duplexes using two well-studied (74) palindromes, TA-DNA (Figure 3A) and AT-DNA (Figure 3B). The major positive signal in both 13C2-labeled TA-DNA and AT-DNA (Figures 3C,D and S1) is an intense band at ∼1720 cm–1 that we preliminarily assign to the localized stretching of TC2═O in a B-form duplex based on values in the experimental literature for isotopically labeled T bases (28,48,49,89) and theoretical calculations. (88) The negative signal at ∼1700 cm–1 is downshifted by the expected amount (∼20 cm–1) for a 12C to 13C mass shift, (37,38) which is well in excess of our instrument’s resolution (set at 4 cm–1).

Figure 3

Figure 3. Isotope editing experiments pinpoint TC2═O IR signals in Watson–Crick base pairs in DNA duplexes. The sequence of the palindromes TA-DNA (A) and AT-DNA (B). Labeled T bases are indicated in red. (C) Light minus heavy IR difference spectrum of 13C2-labeled TA-DNA (black) and AT-DNA (green). Positive bands from 12C2═O and negative bands from 13C2═O are labeled. (D) Enhanced view of the carbonyl region in (C) showing splitting in the minor signal of the AT-DNA duplex. A representative noise line (replicate minus replicate for TA-DNA) is shown in red. The mean of four independent measurements is shown in bold, and the standard deviation in shade.

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We also observe a minor positive signal in each duplex centered at ∼1670 cm–1, whose intensity is roughly one quarter that of the major signal in both duplexes. Interestingly, the two different sequences show differences in this minor signal: in TA-DNA, the signals are broad and in AT-DNA, the signals appear to be splitting into two separate components (Figure 3D). We preliminarily assign the minor signal to delocalized C4═O/C5═C6 stretching with amplitude from the labeled 13C2 atom based on experimental isotope shifts (48) for the isolated T base and theoretical calculations of the A–T base pair. (88) This is consistent with 2DIR studies (24,28) of AT-rich Watson–Crick duplexes that observe four bands in this region due to stretching from both bases, three of which are thought to be due to vibrations localized to the T base and one to adenine. In deuterated buffer, the three from the T base are located at 1690 (C2═O stretching, T2R, which we observe in water as our “major signal” at 1720 cm–1), 1660 (C4═O stretching, T4R), 1640 (T ring stretching, TR), and 1630 cm–1 (adenine ring stretching, AR1). It may be noted that we observe T C5═C6 stretching with our T 13C2 label, resulting in three signals contributing to our difference spectrum. The C═C stretching mode in the T mononucleotide (49) (TR) was found to be fairly localized to the C5 and C6 atoms, but its character may change upon entry into the duplex environment, allowing for it to be observed with our 13C2 isotope. Thus, our “minor signal” in both duplexes may be a composite band containing two overlapping signals: one from TR and the other from T4S. This assignment, and the dependence of the splitting of this signal on the sequence context, will be investigated more deeply in future studies using T 13C4-labeled bases.
The TR stretching mode is also thought to be more sensitive to interstrand base pairing than to intrastrand stacking interactions with its flanking base pairs, as this mode shifts down to 1630 cm–1 upon heating past the duplex melting temperature. (28) Yet, as mentioned, our isotope-edited spectra for these two fully base-paired duplexes show a few differences, the most prominent of which can be seen in the minor positive signal centered at 1670 cm–1. In TA-DNA, this signal is quite broad with a band width at half maximum of ∼30 cm–1. In AT-DNA, the minor ∼1670 cm–1 signal is split into two components: a dominant one at ∼1665 cm–1 and a weak shoulder at ∼1690 cm–1 (Figure 3D).
There are a few physical models that might account for the splitting observed in the minor signal. One is that the minor signal splitting in the T base in AT-DNA experiences two separate H-bonding environments at its C2═O, giving rise to two populations of strongly and weakly bound carbonyls with two different band positions. A previous study using NMR chemical shifts and N–H coupling constants (90) has indicated that the hydrogen bond strength of A–T base pairs may be sequence-dependent and thus our AT-DNA sequence may have weak base pair H-bonding, which in turn can result in the breaking of the Watson–Crick H-bond between C4═O and the adenine −NH2. This results in a small signal due to a population of C4═O that is blue-shifted owing to formation of a nonbonded C4═O. Another possibility that may account for the splitting might arise from the two different sequence contexts experienced by TC4═O in each duplex due to the different sequence contexts for the T base. In TA-DNA, both C2-labeled T bases are adjacent to guanines and are in proximity (about 4 Å) to the guanine C6═O. In AT-DNA, the T bases are flanked with cytosines and are at a much greater distance from the cytosine’s C4═O (about 6 Å). If the TR mode is sensitive to stacking and base pairing, then, different sequence contexts would be expected to shift this mode down, revealing the T4S mode at 1690 cm–1 in AT-DNA.
A third potential model is that the sequence context impacts the character of base modes in DNA duplexes, and thus changes in through-bond coupling between T base modes cannot be rejected completely as the potential source of the splitting. Meanwhile, through-bond coupling due to the frequency shift upon mass labeling is unlikely to be the origin for the splitting, as if this was the case, then the splitting ought to be independent of the sequence context. Future studies using a range of sequence contexts and isotope labels, abasic sites, temperature variance, and 2DIR will aid in discriminating between these physical models.
The edited spectra of TA-DNA and AT-DNA overlay quite well below ∼1600 cm–1, although one additional difference is observed: TA-DNA has two weak signals at 1080 and 1045 cm–1 that are not present in the spectrum of AT-DNA. Signals at this frequency have been attributed to delocalized T ring motions, (48,89) and it is possible that the sequence context has altered the mode’s character such that the C2 atom now contributes a higher percentage of amplitude to the mode in TA-DNA.

3.1.2. Detection of TC2═O IR Signals in Drug-Bound Hoogsteen and Watson–Crick A–T Base Pairs

To test if isotope editing at the T C2 position can isolate signals from atoms in a large DNA/drug complex, and to determine if Hoogsteen base pair formation of A–T base pairs impacts the TC2═O signal, we examined two DNA duplexes when bound to the drug echinomycin (Figure 4A), (74,78,79,91) a peptide inhibitor (92) that possesses anticancer, antiviral, and antibacterial activities. In the TA-DNA duplex, two echinomycin molecules bind to two GC sites (Figure 4A) and induce the formation of tandem A–T Hoogsteen base pairs (Figure 4B) that are sandwiched between the drug-binding sites. In contrast, when echinomycin is bound to the AT-DNA duplex, these tandem AT base pairs maintain Watson–Crick pairing (76,77,79) (Figure 4C). Thus, these two duplexes allow us to test the sensitivity of our edited IR signal to two different types of DNA base pairs, Watson–Crick and Hoogsteen, while simultaneously controlling the presence of the drug as it binds each sequence in an identical manner. Additionally, as echinomycin is an intercalator, binding ought to also remove contributions from stacking: the tandem A–T base pairs are effectively isolated, yet still in a DNA duplex, and this allows us to determine the impact of stacking on the splitting observed in the free duplexes by comparison of the AT-DNA free and drug-bound spectra.

Figure 4

Figure 4. Isolation of the TC2═O stretching signal in a DNA/drug complex with Hoogsteen base pairs. (A) Chemical structure of echinomycin (magenta) and a crystal structure of the bound TA-DNA (PDBID: 1XVN), (91) which induces the formation of two Hoogsteen base pairs (blue). Dashes indicate functional groups from echinomycin close to the labeled carbonyls (distances in angstrom). (B) and (C) GC-step binding sites of echinomycin in TA-DNA are boxed (magenta). Echinomycin was bound to both the light and heavy TA-DNA duplexes and their difference spectra calculated to isolate signals from the two A–T Hoogsteen (T6/T18, blue box) base pairs’ TC2═O stretching signals (see the chemical structure; TC2═O is in red). (D) and (E) Light minus heavy IR difference spectrum of the 13C2-labeled DNA/echinomycin complex with the positive signals from the light isotope labeled. Representative noise lines (replicate minus replicate) are shown in red. The mean of three to four independent measurements is shown in bold, and the standard deviation in shade.

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Labeled and unlabeled TA-DNA and AT-DNA duplexes were bound to echinomycin and the light spectrum subtracted from the T 13C2-labeled spectrum. The extent of binding was determined by examining changes in the IR signals from the DNA backbone and C═O bonds from both echinomycin and DNA (Figure S2) that are characteristic of echinomycin binding, (72) specifically, a decrease in the shoulder at ∼1050 cm–1, an increase at ∼1040 cm–1, an increase at 1740 cm–1, and large increases at ∼1700 cm–1 and between 1650 and 1610 cm–1. Our results (Figures 3C and S3A) show that the difference signal is strong in both the edited spectra, even in the large DNA/drug complex, confirming that our method can be used to isolate C═O signals from specific bases in large, macromolecular complexes.
The major, most intense positive signal observed in the isotope-edited spectra of both drug-bound duplexes are red-shifted by ∼10 cm–1 from their unbound signals from 1720 cm–1 down to ∼1710 cm–1 (Figures 4D,E and S3A,B). This red shift may be due to duplex unwinding upon drug intercalation, allowing water or buffer salts to more deeply penetrate the minor groove, or due to interactions with the drug itself. As can be seen from the crystal structure, there are two carbonyls from the drug relatively close (∼4 Å) to each TC2═O in TA-DNA (Figure 4A), as well as a −CH2 group (∼2.6 Å). The bond dipoles of the drug’s C═O groups are orientated opposite to those of the TC2═Os. Thus, if they interacted with each other, then a blue shift and not a red shift would be expected. (93) We therefore conclude that the source of the ∼10 cm–1 red shift in both drug-bound duplexes relative to the free DNA likely arises from increased H-bonding from solvent waters to C2═O as the minor groove is widened by echinomycin. This red shift may also arise from destacking due to drug intercalation, which effectively “deletes” interactions between the T base and the neighboring base; however, shifts due to stacking are not anticipated to result in such a strong red shift. (94) These hypotheses will be tested further using D2O exchange in future studies to determine if there is an observable isotope shift and inserting abasic sites flanking the isotopically labeled base, which ought to remove any stacking.
Interestingly, the minor signal observed at ∼1670 cm–1 in the free TA-DNA duplex dramatically splits when echinomycin is bound and Hoogsteen base pairs are formed into two components at ∼1690 and ∼1655 cm–1 (see Figure S3A for an overlay of the drug-bound and free TA-DNA). Meanwhile the AT-DNA/echinomycin complex, which is bound to the drug in an identical fashion to TA-DNA but preserves the Watson–Crick base pairs when bound, exhibits a single minor signal at ∼1665 cm–1 (see Figure S3B for an overlay of the drug-bound and free AT-DNA). As with the free duplexes, the physical origins of this minor-band splitting in the drug-induced Hoogsteen base pairs may arise from different mechanisms (assuming that this mode arises from the T4S and TR modes, with minor participation from the 13C2-labeled atom). If we ascribe the ∼1690 cm–1 signal once again to T4S, this would imply that the TR mode downshifts by ∼15 cm–1 in the drug-induced Hoogsteen base pair formed in the TA-DNA/drug complex. This is in line with a previous study, (28) indicating that this T ring mode is sensitive to base pairing.
Many 2DIR studies (23,25,26) have illustrated that coupling between vibrational modes is a major determinant of why IR spectroscopy is sensitive to DNA structure and base paring. Splitting in duplexes may arise from both interactions with modes located within flanking bases and interactions with modes located on its base-pairing partner. (25,94) A recent theoretical study (94) indicates that in WC A–T pairs, T modes are coupled to ring C═C bond vibrations in the partnering adenine, and this has also been observed using 2DIR spectroscopy. (24,28,95−97) This coupling would likely be impacted by the flipping of the adenine base from anti to syn in the Hoogsteen base pair, which switches the orientation of the adenine ring. Future experiments on these duplexes using 13C4-labeled T will aid not only in the interpretation of this splitting but also in the validation of its suitability for use as a marker band for A–T Hoogsteen base pairs.
Finally, it is worth noting another signal centered at ∼1605 cm–1 (broad in TA-DNA and narrow in AT-DNA) that is present in both bound duplexes and absent in the free duplexes, the origins of which are not clear. This may be due to adenine −NH2 scissoring, as computational studies indicate that base modes in general can become highly delocalized upon base pairing (88) and modes can contain contributions from both bases. Thus, our labeled T 13C2 atom may participate in adenine vibrations (such as amino scissoring) that would be expected to be impacted by drug binding. Future studies with 13C4═O isotope and isotopes on the adenine and T ring atoms and complimentary 2DIR studies will aid in the assignment of these minor signals and provide physical interpretations for the observed splitting.

3.1.3. Detection of TC2═O Signals in Singly13C-Labeled Watson–Crick and m1A-Hoogsteen Base Pairs

As mentioned, both the TA- and AT-DNA duplexes are palindromic and so contain two 13C-labeled carbon atoms. To test if the IR difference signal arising from a single 13C-labeled atom in a large 12-mer DNA duplex is detectable above the noise for the measurement and to examine if the observed frequency is altered when changing the sequence context, we incorporated a 13C2 T base into the A6-DNA duplex (Figure 5A). To determine if the splitting observed in the drug-induced Hoogsteens in TA-DNA arises from the drug or from Hoogsteen formation, we installed an N1-methyladenine (m1A, Figure 5B), which is a known form of DNA damage, (98) opposite the labeled T base. The addition of the methyl on the N1 of adenine (Figure 5B) results in a positive charge being placed on the base, and a steric clash with the T N3–H forces it to flip 180° and form Hoogsteen H-bonds. (99−106)

Figure 5

Figure 5. Isotope editing pinpoints a single T atom in two DNA duplexes. (A) Sequence of A6-DNA with the labeled T (T9) in red. (B) Chemical structure of N1-methyladenine (m1A) incorporated at A16, opposite the 13C2-labeled T (red). Methyl group on the adenine N1 has a steric clash with the T N3–H, resulting in the purine flipping over into its Hoogsteen form. (C) Light minus heavy difference spectra of A6-DNA (black) and m1A-A6-DNA (blue).

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In the isotope-edited spectra of T 13C2-labeled A6-DNA, the signal is ∼50% that of the doubly labeled T 13C2s in TA and AT-DNA but quite detectable above the noise for the measurement (Figure 5C). The A6-DNA difference spectrum is almost identical to that of TA-DNA (see Figure S4A for overlays of the A6-DNA, TA-DNA, and AT-DNA spectra), with a major signal at 1720 cm–1 and a broad minor signal at ∼1670 cm–1. In m1A-A6-DNA (Figure 5C), the major signal maintains its position at 1720 cm–1. As in the drug-bound, Hoogsteen-forming TA-DNA duplex, the minor signal at 1670 cm–1 is split into two bands (see Figure S4B for an overlay of m1A-A6-DNA with the bound TA-DNA), with one now at ∼1680 cm–1 and the other at ∼1655 cm–1. The ∼1680 cm–1 band is ∼10 cm–1 red-shifted from the signal observed in the nonchemically enforced Hoogsteen base pairs formed in the TA-DNA/echinomycin complex. This may be due to the positive charge on the chemically modified m1A base, which could increase the strength of the H-bond between TC4═O and the adenine −NH2 and in turn lower the frequency of the T4S stretch.
Taking together the results from the m1A-A6-DNA duplex and from the free TA-DNA and AT-DNA duplexes, we conclude that Hoogsteen H-bonding does not alter the frequency of the major TC2═O stretching signal, whose position is thus far independent of the sequence context and base pairing but does appear to be sensitive to the H-bonding environment in the minor groove. Meanwhile, the strong red shift down to ∼1655 cm–1 observed in the minor signal in both drug-induced and chemically enforced A–T Hoogsteen base pairs (Figure S4B) is not observed in either drug-bound or free WC base pairs (see Figure S4A for overlays) and may arise solely from either a different coupling from T base modes to adenine ring vibrations in a syn vs an anti adenine or due to increased H-bonding at TC4═O in a chemical-enforced Hoogsteen base pair. Either way, this splitting may therefore be suitable for use as a marker band for detecting protein-bound A–T Hoogsteen pairs in solution. We note that our short duplexes have about equal AT-to-GC content (six A–T pairs in TA- and AT-DNA and seven A–T pairs in A6-DNA), and so studies that dramatically change the AT-to-GC ratios of the sequence along with studies on much longer duplexes must be performed to determine the limits of detection in our isotope-edited spectra.

3.2. Sensitivity of TC2═O IR Signals to the Solvent Environment

3.2.1. Solvatochromatic Studies of TC2═O and Its Sensitivity to Solvent H-Bonding

The isotope editing experiments provide a means to measure the frequency of TC2═O in solution-state DNA duplexes, but calibration is required to determine if this band position changes as a function of the strength of H-bonding to C2═O. To provide an initial interpretation for the relative strength of interactions at TC2═O in a duplex environment, we measured IR spectra of the T base in solvents with different H-bonding abilities. We also crystallized the 9-methyladenine/1-methylthymine dimer from Hoogsteen’s original paper (5,47) and measured its IR spectrum. (The IR spectrum of Hoogsteen A–T crystals was examined in earlier studies; (107,108) however, the sample was either too thick for a transmission measurement in the 1800–1300 cm–1 region (109) or only the amide stretching region was examined.) (108) If this CH···O H-bond exists in Watson–Crick and/or Hoogsteen base pairs, then the frequency of C2═O ought to be greater than 1720 cm–1 in solvents with decreased H-bonding power, as measured by Gutmann’s H-bond acceptor number (AN) (110) for the given solvent. Our solvatochromatic results are in line with those of previous studies using Raman spectroscopy, (111) reporting that both T C═O stretching signals are sensitive to solvent H-bond strength.
The highest frequency signal of the T base (when not in a duplex) has been shown via isotope labeling studies to arise from localized C2═O stretching in its Raman and IR spectra. (48,89) We plotted the highest positions (Figure S5A,B) vs the H-bond acceptor number of the solvent in which T was dissolved (Figure 6). We used the equation obtained from a linear regression of these data to calculate the AN values for the band positions that we observed via T 13C2 isotope editing in the DNA duplexes, the 9-methyladenine/1-methylthymine Hoogsteen crystal, and the isolated N1-methylthymine’s observed IR position in an argon matrix (from ref (112) (112)). We find that in solvents with diminished H-bonding power such as d6-DMSO (AN = 21), the C2═O signal lies at ∼1750 cm–1, while in strong H-bonding solvents like water (AN = 54), the signal is shifted down to ∼1695 cm–1.

Figure 6

Figure 6. Acceptor numbers for A–T base pairs in DNA duplexes. A plot of the solvent’s Gutmann H-bond acceptor number (AN) vs the observed TC2═O stretching. Values for 13C2-labeled duplexes, the Hoogsteen crystal, and the isolated matrix N1-methylthymine were calculated based on the regression line derived from the observed values for the T base in water, dimethylformamide (DMF), and d6-dimethyl sulfoxide (d6-DMSO). The isolated matrix value is from N1-methylthymine in the study by Person and co-workers. (112)

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In the 9-methyladenine/1-methylthymine dimer crystal, which crystallizes with Hoogsteen H-bonding (Figure S6A,B), (5,47) the IR position of TC2═O is about the same as that observed in water (Figure S6C), which might indicate a very strong CH···O H-bond. However, in our structure, the measured distance between the carbon and oxygen atoms is 3.664 Å, which is just under the typical cutoff distance. Upon inspection of the crystal packing (Figure S6B), we observed another H-bonding interaction between TC2═O and an adenine −NH2 group from an adjacent unit cell, which is likely the source of the strong red shift in the Hoogsteen crystal and supports our hypothesis that TC2═O stretching is a robust probe of the H-bonding environment.
In summary, the frequency of C2═O is shifted down in energy by ∼30 cm–1 when in a Watson–Crick or a Hoogsteen H-bond in a DNA duplex from its position in d6-DMSO, indicating that C2═O experiences a H-bond interaction in DNA duplexes in both WC and Hoogsteen base pairs whose strength is less than that of water. This red shift in the paired duplex from the d6-DMSO and the isolation matrix values is consistent with either a CH···O interaction with the adenine C2/C8–H (Figure 6), which has been observed in nucleic acid crystal structures, (113) or a weakly bound water molecule forming the spine of hydration (55−57,97) in the minor groove of the duplexes.

3.3. Calculations of the CH···O Bond Strength for A–T Base Pairs

3.3.1. Ab Initio Calculations of the CH···O Bond in A–T Base Pairs

To investigate the energetics of the CH···O interaction, we performed MP2 correlated calculations using several different A–T base pair coordinates. One set used the PDB coordinates (PDBID: 2ADW) for a DNA sequence bound to echinomycin that contained two duplexes in the unit cell, one of which had WC A–T pairs and the other had Hoogsteen pairs (Figure S7A), so that energies could be effectively compared when in drug-bound DNA. The other set used NMR coordinates (101,114) for the A16–T9 base pair in the A6-DNA (PDBID: 5UZF) and m1A-A6-DNA (PDBID: 5UZI, methyl group has been removed) (Figure S7B) duplexes. Interaction energies were assessed as the difference between the energy of each base pair and the sum of the two monomers.
We evaluated the interaction energy of the Watson–Crick and Hoogsteen dimers (Table 1), which were then compared to two controls to estimate the strength of the CH···O bonds. In one control, the C2/8H···O interaction is abrogated by substitution of the C2 or C8 with a N atom (Figure S7C). This loss of the CH···O H-bond reduces the interaction energy by 2.2–3.8 kcal/mol. In the other control, we rotated the T base by 90° out of the joint plane, around the CH···OC axis, so that the two canonical H-bonds are deleted (Figure S7D) and the CH···O interaction is the only remaining H-bond in the dimer system.
Table 1. Interaction Energies (Eint, kcal/mol) for Watson–Crick and Hoogsteen A–T Base Pairs for Echinomycin-Bound DNA (PDBID: 2ADW) and the NMR Structures for A6-DNA (PDBID: 5UZF) and m1A6-DNA (PDBID: 5UZI), along with AIM Electron Densities (au) for the H-Bond Path Critical Points
 Eint (kcal/mol)ρBCP (au)
 A–T pairC–H to Nachange90° rotbA–NH···O–TT–NH···N–AA–CH···O–T
WC (2ADW)13.0610.51–2.550.640.03080.03750.0047
Hoogsteen (2ADW)13.7910.46–3.331.450.02420.03500.0045
WC (5UZF)12.9610.72–2.24–0.100.02810.04120.0036
Hoogsteen (5UZI)13.549.71–3.830.280.02460.04270.0042
a

The change of C2/C8–H of adenine to N removes possible CH···O H-bonds.

b

Rotation of T around φ(A–CH···OC–T) to 90° so as to destroy NH···O and NH···N HBs and retain only CH···O.

In addition to removing the canonical H-bonds, this rotation also takes the two bases out of their coplanar arrangement and so has an additional destabilizing impact on the system’s energy. Nonetheless, the interaction energy remains attractive by as much as 1.5 kcal/mol, which must be attributed to the remaining CH···O H-bond, and is in agreement with similar analyses (115,116) performed on idealized A–T base pairs to determine the relative energy contributions of this bond. Altogether, the interaction energies from both the crystal and NMR (Table 1) coordinates are consistent with the existence of a weak CH···O H-bond. This is consistent with the frequency we observe in the duplexes (1720 cm–1) being greater than the value in water (1700 cm–1) and lower than that in d6-DMSO (∼1750 cm–1).
An atoms-in-molecules (AIM) analysis of the electron density at various H-bond critical points allows for an independent assessment of H-bond strengths, along with the H-bond lengths. As seen in Table 1, these densities are in the range of 0.025–0.043 au for the pair of canonical H-bonds, with NH···N slightly stronger than NH···O. But of the greatest importance here is that there is a bond path in all four systems linking the CH group with the O, consistent with its characterization as a H-bond. In keeping with the hypothesis that this bond is weaker than its canonical analogues, its critical point density is smaller but nonetheless falls within the range expected for a weak H-bond.
From these results, we conclude that there is a weak CH···O H-bond present in A–T WC and Hoogsteen base pairs. A few DFT studies on A–T WC base pairs have strongly disputed (52−54) the existence of a CH2/8···O H-bond, but later studies have indicated that it is present (117,118) although weak. Our experimental and theoretical results are in line with those of previous theoretical studies that support the existence of a third H-bond in A–T base pairs.

4. Discussion

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Here, we describe a powerful method for isolating carbonyl vibrational frequencies from the highly congested IR spectra of DNA duplexes and DNA/drug complexes in aqueous solution. This in conjunction with plots relating the change in band position to the H-bonding strength of a solvent and allowing us to make qualitative statements about the H-bonding status of TC2═O in DNA duplexes in solution. A previous study (119) incorporating modified adenines containing a N atom at the C2 position, which is incapable of H-bonding with TC2═O, reported a decrease in duplex melting temperature by 5 °C per modified base incorporated. The authors state that this may be due to interruption of the hydration spine of water present in duplexes or the repulsive interactions between the N and O atom lone pairs. Their observed decrease in the duplex melting temperature may also be due to interruption of a CH···O H-bond, the loss of which starts to destabilize the duplex. They noted that destabilization appeared to be independent of the sequence, which is consistent with our present results indicating that the position of the major TC2═O signal is unchanged with the sequence context. Base pair melting is an important parameter for cellular processes that require genomic DNA to be single-stranded such as replication, and thus this potential CH···O H-bond may supply a weak, sequence-independent energetic barrier for localized duplex melting.
Additionally, 2DIR studies also indicate that the TC2═O stretching motion may be a good reporter for minor groove interactions (such as with the spine of hydration) in general, (97) and our results showing a red shift in this signal in our drug-bound duplexes support this conclusion. Every TC2═O stretching frequency in naked DNA duplexes that we have measured thus far has a frequency of 1720 cm–1 and so the “acceptor number” for TC2═O in a duplex environment (∼40) lies midway between those of DMSO (AN = 21) and water (AN = 54). While the adenine C2/H8 is not as strong as one of the most powerful H-bonders, liquid water, it is significantly stronger than DMSO. We therefore conclude that our observations thus far are consistent with a CH···O H-bond in A–T base pairs which is weak, but present, and could contribute to base-pair stability. Our DFT calculations support this conclusion and indicate that the energy of this bond (as compared to the unpaired A and T monomers) is ∼2 kcal/mol, supporting the conclusion that the bond is weak but certainly present and likely to contribute to the base pair’s stability.
It must be noted, however, that this is a qualitative interpretation as calculated T vibrational modes are well-known to change dramatically (particularly in the degree of their delocalization over multiple atoms) (88) when going from a T monomer to the base-paired, duplex environment. Furthermore, at present, we cannot rule out H-bonding interactions with TC2═O from the spine of hydration (55−63) observed in the minor groove in duplex crystal structures whose existence in solution is supported by a number of solution NMR (64,65) and 2DIR (66−69) experiments and molecular dynamics simulations. (70,71) Thus, the position of the C2═O signal in our isotope editing IR experiments may arise from interaction with a weakly bound water molecule in the minor grove. However, the positions of the waters in the spine of hydration are thought to be sequence-dependent. (120−122) If a water molecule from the spine of hydration were to impact the position of the IR signal, then we would have expected increases or decreases in wavenumber as a function of sequence as TC2═O experiences increases or decreases in H-bonding. We do not observe such changes, supporting the conclusion that there is a weak CH···O interaction between TC2═O and adenine.

5. Conclusions

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In summary, we have demonstrated that 13C isotope editing at TC2═O can be used to isolate the stretching frequency of this carbonyl from the congested IR spectrum of DNA duplexes and DNA/drug complexes. Our solvatochromatic experiments combined with our isotope editing results are thus far consistent with a weak CH···O interaction with the TC2═O bond in both Watson–Crick and Hoogsteen A–T base pairs. Future work will employ labeling with isotopes at different positions to assign the major signal to the TC2═O signal in a DNA duplex and variable temperature studies to quantify the relationship between H-bond enthalpy and carbonyl stretches in DNA bases. D2O exchange studies will be conducted to probe the exposure of TC2═O to solvent waters. These may be combined with isotope editing experiments utilizing C2/8-D labeled adenine to observe mass shifts and determine the extent to which this TC2═O bond is H-bonded to water vs the adenine C2/8H.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jpcb.1c01351.

  • Synthesis of 13C2-labeled thymine phosphoramidite; crystallographic information for the 9-methyladenine/1-methylthymine dimer; full IR spectrum of unlabeled TA-DNA and the fully 15N, 13C labeled and 13C2 labaled T isotopes; full IR spectra of free and bound AT-DNA; overlays of the isotope-edited spectra for all DNA duplexes examined in this work; observed density map for crystals of the N9-methyladenine and N1-methylthymine Hoogsteen dimers; and models and controls used in the ab initio calculations for Watson–Crick and Hoogsteen A–T base pairs (PDF)

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Author Information

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  • Corresponding Author
    • Allison L. Stelling - Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States;  Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States;  Orcidhttps://orcid.org/0000-0002-0368-0852;  Email: [email protected]
  • Authors
    • Robert J. Fick - Department of Chemistry and Biochemistry, The University of Texas at Dallas, Richardson, Texas 75080, United States
    • Amy Y. Liu - Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
    • Felix Nussbaumer - Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria
    • Christoph Kreutz - Institute of Organic Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck 6020, Austria;  Orcidhttps://orcid.org/0000-0002-7018-9326
    • Atul Rangadurai - Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, United States
    • Yu Xu - Department of Chemistry, Duke University, Durham, North Carolina 27710, United States
    • Roger D. Sommer - Molecular Education, Technology, and Research Innovation Center, North Carolina State University, Raleigh, North Carolina 27695, United States;  Orcidhttps://orcid.org/0000-0003-1422-5967
    • Honglue Shi - Department of Chemistry, Duke University, Durham, North Carolina 27710, United States;  Orcidhttps://orcid.org/0000-0003-3847-1652
    • Steve Scheiner - Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322, United States;  Orcidhttps://orcid.org/0000-0003-0793-0369
  • Funding

    This work was supported by the National Institutes of Health [1F32GM125213-01 and 5F32GM125213-02 to A.L.S.; A.R., H.S., and Y.X. were supported by R01GM089846], and C.K. was supported by the Austrian Science Fund (FWF, projects P30370 and P32773) and Austrian Research Promotion Agency FFG (West Austrian BioNMR, 858017).

  • Notes
    The authors declare no competing financial interest.

    Atomic coordinates for the 9-methyladenine/1-methylthymine crystal have been deposited in the Cambridge Crystallographic Data Centre under deposition number 2053806.

Acknowledgments

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We are grateful for critical commentary and many useful discussions with Prof. Al-Hashimi and members of the Al-Hashimi laboratory at Duke University, Prof. Trievel at the University of Michigan (Ann Arbor), and Prof. Horowitz at the University of Denver. We additionally thank Prof. Moran at Southern Illinois University at Carbondale for many useful discussions concerning the impact of vibrational coupling in nucleic acids. This work was performed in part by the Molecular Education, Technology and Research Innovation Center (METRIC) at NC State University, which is supported by the State of North Carolina. A.L.S. thanks the Al-Hashimi laboratory, the Department of Biochemistry at Duke University Medical Center, and the Department of Chemistry and Biochemistry at the University of Texas at Dallas for support.

Abbreviations

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T

thymine

A

adenine

C

cytosine

G

guanine

WC

Watson–Crick

References

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This article references 122 other publications.

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    The traditional Watson-Crick base pairs in DNA may occasionally adopt a Hoogsteen conformation, with a different organization of hydrogen bonds. Previous crystal structures have shown that the Hoogsteen conformation is favored in alternating AT sequences of DNA. Here we present new data for a different sequence, d(ATTAAT)2, which is also found in the Hoogsteen conformation. Thus we demonstrate that other all-AT sequences of DNA with a different sequence may be found in the Hoogsteen conformation. We conclude that any all-AT sequence might acquire this conformation under appropriate conditions. We also compare the detailed features of DNA in either the Hoogsteen or Watson-Crick conformations.
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  3. 3
    Abrescia, N. G. A.; Thompson, A.; Huynh-Dinh, T.; Subirana, J. A. Crystal structure of an antiparallel DNA fragment with Hoogsteen base pairing. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 2806– 2811,  DOI: 10.1073/pnas.052675499
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    3
    Crystal structure of an antiparallel DNA fragment with Hoogsteen base pairing
    Abrescia, Nicola G. A.; Thompson, Andrew; Huynh-Dinh, Tam; Subirana, Juan A.
    Proceedings of the National Academy of Sciences of the United States of America (2002), 99 (5), 2806-2811CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    We report here an alternative double-helical structure of the DNA mol. It has been found in the d(ATABrUAT) and d(ATATAT) sequences by single-crystal x-ray crystallog. This sequence is found not only in TATA boxes, but also in other regulatory regions of DNA. Bases of the two antiparallel strands form Hoogsteen pairs, with adenines in the syn conformation. The structure is related neither to those found in triple helixes nor to parallel DNA duplexes. Its conformational parameters are very similar to those of duplex DNA in the B form. Both forms may coexist under physiol. conditions, although the Hoogsteen pairing greatly influences the recognition sites on DNA. Our results demonstrate that an alternative to the classical B-DNA double helix is possible.
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  4. 4
    Hoogsteen, K. R. The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine. Acta Crystallogr. 1963, 16, 907– 916,  DOI: 10.1107/S0365110X63002437
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    4
    The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine
    Hoogsteen, Karst
    Acta Crystallographica (1963), 16 (9), 907-16CODEN: ACCRA9; ISSN:0365-110X.
    Crystals of a 1:1 H-bonded complex between 1-methylthymine and 9-methyladenine can be grown from an aq. soln. contg. equimol. quantities of the 2 compds. The crystals are monoclinic, with a 8.304, b 6.552, c 12.837 A. and β = 106° 50'. The space group is P21/m, with 2 base-pair complexes in the unit cell. The structure was refined with 3-dimensional data taken with Cu-radiation. The positional coordinates and anisotropic temp. factors of the heavy atoms were obtained by least-sqs. analyses. The H atoms, except those of 2 Me groups, were located from a 3-dimensional difference Fourier synthesis. The 1-methylthymine and 9-methyladenine mols. form a planar base pair lying in a mirror plane and are connected to one another by 2 nearly linear H bonds, from the NH2 group of 9-methyladenine to O(9) of 1-methylthymine (2.846 A.) and N(3) of 1-methylthymine to N(7) of 9-methyladenine (2.924 A.). This structure differs from the adenine-thymine pairing proposed by Watson and Crick [Nature 171, 737 (1953)], where N3 of thymine is H-bonded to N1 of adenine. The distance between the Me group at N1 of 1-methylthymine and the one at N9 of 9-methyladenine is 8.645 A., whereas this distance is 11.1 A. in the pairing proposed by W. and C. (CA 48, 5113d).
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  5. 5
    Hoogsteen, K. The structure of crystals containing a hydrogen-bonded complex of 1-methylthymine and 9-methyladenine. Acta Crystallogr. 1959, 12, 822,  DOI: 10.1107/S0365110X59002389
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    5
    The structure of crystals containing a hydrogen-bonded complex of 1-methylthymine and 9-methyladenine
    Hoogsteen, Karst
    Acta Crystallographica (1959), 12 (), 822-3CODEN: ACCRA9; ISSN:0365-110X.
    Prismatic crystals of 1-methylthymine (I), crystd. from aq. soln. at room temp., are monoclinic, space group P21/c, with 4 mols. per unit cell; a = 7.11, b = 11.96, c = 7.52 A., β = 90°, d. (exptl.) = 1.415. Needles of 9-methyladenine (II), crystd. in the same way, are monoclinic, space group P21/c, with 4 mols. per unit cell; a = 7.67, b = 12.24, c = 8.47 A., β = 123°26', d. (exptl.) = 1.471. When equimol. mixts. of I and II were crystd. from aq. soln., monoclinic needles resulted, with unit-cell dimensions: a = 8.28, b = 6.51, c = 12.75 A., β = 106°48', d. (exptl.) = 1.433. The probable space group is P21/m. There are 2 asym. units per unit cell, with each asym. unit composed of one mol. each of I and II. The C, N, and O atoms lie in the mirror plane. H-bonding occurs between N3 of I and N7 of II, and between the O on C4 of I and the amino N of II. Adjacent complex units are held together by H bonds between the amino N of II and the O on C2 of I.
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  6. 6
    Abrescia, N. G. A.; Gonzalez, C.; Gouyette, C.; Subirana, J. A. X-ray and NMR Studies of the DNA Oligomer d(ATATAT): Hoogsteen Base Pairing in Duplex DNA. Biochemistry 2004, 43, 4092– 4100,  DOI: 10.1021/bi0355140
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    6
    X-ray and NMR Studies of the DNA Oligomer d(ATATAT): Hoogsteen Base Pairing in Duplex DNA
    Abrescia, Nicola G. A.; Gonzalez, Carlos; Gouyette, Catherine; Subirana, Juan A.
    Biochemistry (2004), 43 (14), 4092-4100CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    We present and analyze the structure of the oligonucleotide d(ATATAT) found in two different forms by X-ray crystallog. and in soln. by NMR. We find that in both crystal lattices the oligonucleotide forms an antiparallel double helical duplex in which base pairing is of the Hoogsteen type. The double helix is apparently very similar to the std. B-form of DNA, with about 10 base pairs per turn. However, the adenines in the duplex are flipped over; as a result, the physicochem. features of both grooves of the helix are changed. In particular, the minor groove is narrow and hydrophobic. On the other hand, d(ATATAT) displays a propensity to adopt the B conformation in soln. These results confirm the polymorphism of AT-rich sequences in DNA. Furthermore, we show that extrahelical adenines and thymines can be minor groove binders in Hoogsteen DNA.
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  7. 7
    Stelling, A. L.; Liu, A. Y.; Zeng, W.; Salinas, R.; Schumacher, M. A.; Al-Hashimi, H. M. Infrared Spectroscopic Observation of a G–C+ Hoogsteen Base Pair in the DNA:TATA-Box Binding Protein Complex Under Solution Conditions. Angew. Chem., Int. Ed. 2019, 58, 12010– 12013,  DOI: 10.1002/anie.201902693
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    7
    Infrared Spectroscopic Observation of a G-C+ Hoogsteen Base Pair in the DNA:TATA-Box Binding Protein Complex Under Solution Conditions
    Stelling, Allison L.; Liu, Amy Y.; Zeng, Wenjie; Salinas, Raul; Schumacher, Maria A.; Al-Hashimi, Hashim M.
    Angewandte Chemie, International Edition (2019), 58 (35), 12010-12013CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Hoogsteen DNA base pairs (bps) are an alternative base pairing to canonical Watson-Crick bps and are thought to play important biochem. roles. Hoogsteen bps have been reported in a handful of X-ray structures of protein-DNA complexes. However, there are several examples of Hoogsteen bps in crystal structures that form Watson-Crick bps when examd. under soln. conditions. Furthermore, Hoogsteen bps can sometimes be difficult to resolve in DNA:protein complexes by X-ray crystallog. due to ambiguous electron d. and by soln.-state NMR spectroscopy due to size limitations. Here, using IR spectroscopy, we report the first direct soln.-state observation of a Hoogsteen (G-C+) bp in a DNA:protein complex under soln. conditions with specific application to DNA-bound TATA-box binding protein. These results support a previous assignment of a G-C+ Hoogsteen bp in the complex, and indicate that Hoogsteen bps do indeed exist under soln. conditions in DNA:protein complexes.
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  8. 8
    Thijs, R.; Zeegers-Huyskens, T. Infrared and Raman studies of hydrogen bonded complexes involving acetone, acetophenone and benzophenone—II. Raman intensity of the vC═O band. Spectrochim. Acta, Part A 1984, 40, 1057– 1061,  DOI: 10.1016/0584-8539(84)80133-6
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    8
    Infrared and Raman studies of hydrogen bonded complexes involving acetone, acetophenone and benzophenone - II. Raman intensity of the ν C:O band
    Thijs, R.; Zeegers-Huyskens, T.
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (1984), 40A (11-12), 1057-61CODEN: SAMCAS; ISSN:0584-8539.
    The effect of H bond formation on the Raman intensity of the νC:O band of Me2CO, acetophenone, and benzophenone complexed with PhOH derivs. (pKα = 10.30-7.75) was investigated. The Raman intensity enhancement brought about by complex formation lies between 1.1 and 2.5 and is inversely related to the Raman intensity in the free base. Linear correlations were found between the square root of the intensity enhancement and the enthalpy of complex formation, the intercepts and the slopes depending on the nature of the proton acceptor. The depolarization ratio of the carbonyl band remains practically unchanged. The results are discussed in terms of σ and π electronic densities on the C and O atoms of the carbonyl function.
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  9. 9
    Lewell, X. Q.; Hillier, I. H.; Field, M. J.; Morris, J. J.; Taylor, P. J. Theoretical studies of vibrational frequency shifts upon hydrogen bonding. The carbonyl stretching mode in complexes of formaldehyde. J. Chem. Soc., Faraday Trans. 2 1988, 84, 893– 898,  DOI: 10.1039/f29888400893
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    9
    Theoretical studies of vibrational frequency shifts upon hydrogen bonding: the carbonyl stretching mode in complexes of formaldehyde
    Lewell, Xiao Q.; Hillier, Ian H.; Field, Martin J.; Morris, Jeffrey J.; Taylor, Peter J.
    Journal of the Chemical Society, Faraday Transactions 2: Molecular and Chemical Physics (1988), 84 (7), 893-8CODEN: JCFTBS; ISSN:0300-9238.
    The shifts in the vibrational frequencies of formaldehyde and water upon formation of the H-bonded complex were calcd. using ab initio MO wave functions and STO-3G, 3-21G, 6-31G and 6-31G** basis sets, and were compared with exptl. values. The shifts in the H2CO frequencies are given best in the STO-3G basis, but the 6-31G** basis is needed to predict the changes in the water frequencies accurately. For a series of complexes involving H2CO, studied at the STO-3G level, a linear relation was found between the calcd. H bond strength and the shift in the CO stretching frequency.
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  10. 10
    Rodríguez Ortega, P. G.; Montejo, M.; Valera, M. S.; López González, J. J. Studying the Effect of Temperature on the Formation of Hydrogen Bond Dimers: A FTIR and Computational Chemistry Lab for Undergraduate Students. J. Chem. Educ. 2019, 96, 1760– 1766,  DOI: 10.1021/acs.jchemed.9b00237
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    10
    Studying the Effect of Temperature on the Formation of Hydrogen Bond Dimers: A FTIR and Computational Chemistry Lab for Undergraduate Students
    Rodriguez Ortega, P. G.; Montejo, M.; Valera, M. S.; Lopez Gonzalez, J. J.
    Journal of Chemical Education (2019), 96 (8), 1760-1766CODEN: JCEDA8; ISSN:0021-9584. (American Chemical Society and Division of Chemical Education, Inc.)
    This lab. expt. allows one to study the effect of temp. in the process of formation of hydrogen bound cyclic dimers of benzoic acid (BA). The implementation of the proposed methodol., which comprises the use of FTIR spectroscopy and quantum chem. calcns., enables the obtaining of the thermodn. parameters of the dimerization reaction and their subsequent validation by computational chem. calcns. Hence, the students are involved in a practical learning scheme focused in the study of a central topic in chem., such as hydrogen bonding, with the final purpose being to train chem. students in applying theor.-exptl. approaches to ext. meaningful data and valuable information for explaining exptl. observables.
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  11. 11
    Chen, J.-S.; Wu, C.-C.; Kao, D.-Y. New approach to IR study of monomer–dimer self-association: 2,2-dimethyl-3-ethyl-3-pentanol in tetrachloroethylene as an example. Spectrochim. Acta, Part A 2004, 60, 2287– 2293,  DOI: 10.1016/j.saa.2003.12.002
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    11
    New approach to IR study of monomer-dimer self-association: 2,2-dimethyl-3-ethyl-3-pentanol in tetrachloroethylene as an example
    Chen, Jenn-Shing; Wu, Cheng-Chang; Kao, Dah-Yu
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2004), 60A (10), 2287-2293CODEN: SAMCAS; ISSN:1386-1425. (Elsevier)
    The dimerization of 2,2-dimethyl-3-ethyl-3-pentanol in tetrachloroethylene in the dild. region has been studied at 4 temps. by IR spectroscopy. The aforementioned solute compd. is chosen because self-assocn. beyond dimerization is hampered by the steric hindrance generated by the bulky sidechains. The integrated absorbances of the monomer bands were treated to obtain its molar absorptivity and dimerization const. The same dimerization const. as well as the molar absorptivity of dimer band can be obtained from the data treatment of the integrated absorbances of the dimer band. The disparity between two values of dimerization const. detd. by two independent sources offers an opportunity to check the consistency of the detn. The std. enthalpy and entropy of dimerization have also been calcd. by means of van't Hoff plot, resp., from the data of temp.-dependent dimerization consts. obtained from the monomer bands and dimer bands.
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  12. 12
    Pazos, I. M.; Ghosh, A.; Tucker, M. J.; Gai, F. Ester Carbonyl Vibration as a Sensitive Probe of Protein Local Electric Field. Angew. Chem., Int. Ed. 2014, 53, 6080– 6084,  DOI: 10.1002/anie.201402011
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    12
    Ester Carbonyl Vibration as a Sensitive Probe of Protein Local Electric Field
    Pazos, Ileana M.; Ghosh, Ayanjeet; Tucker, Matthew J.; Gai, Feng
    Angewandte Chemie, International Edition (2014), 53 (24), 6080-6084CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The ability to quantify the local electrostatic environment of proteins and protein/peptide assemblies is key to gaining a microscopic understanding of many biol. interactions and processes. Herein, we show that the ester carbonyl stretching vibration of two non-natural amino acids, L-aspartic acid 4-Me ester and L-glutamic acid 5-Me ester, is a convenient and sensitive probe in this regard, since its frequency correlates linearly with the local electrostatic field for both hydrogen-bonding and non-hydrogen-bonding environments. We expect that the resultant frequency-elec.-field map will find use in various applications. Furthermore, we show that, when situated in a non-hydrogen-bonding environment, this probe can also be used to measure the local dielec. const. (ε). For example, its application to amyloid fibrils formed by Aβ16-22 revealed that the interior of such β-sheet assemblies has an ε value of approx. 5.6.
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  13. 13
    Deng, H. Chapter Five - Enzyme Active Site Interactions by Raman/FTIR, NMR, and Ab Initio Calculations. In Advances in Protein Chemistry and Structural Biology, Christov, C. Z., Ed.; Academic Press, 2013; Vol. 93, pp 153– 182.
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  14. 14
    Schneider, S. H.; Boxer, S. G. Vibrational Stark Effects of Carbonyl Probes Applied to Reinterpret IR and Raman Data for Enzyme Inhibitors in Terms of Electric Fields at the Active Site. J. Phys. Chem. B 2016, 120, 9672– 9684,  DOI: 10.1021/acs.jpcb.6b08133
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    14
    Vibrational Stark Effects of Carbonyl Probes Applied to Reinterpret IR and Raman Data for Enzyme Inhibitors in Terms of Electric Fields at the Active Site
    Schneider, Samuel H.; Boxer, Steven G.
    Journal of Physical Chemistry B (2016), 120 (36), 9672-9684CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    IR and Raman frequency shifts have been reported for numerous probes of enzyme transition states, leading to diverse interpretations. In the case of the model enzyme, ketosteroid isomerase (KSI), the authors have previously argued that IR spectral shifts for a carbonyl probe at the active site can provide a connection between the active site elec. field and the activation free energy. Here, the authors generalized this approach to a much broader set of carbonyl probes (e.g., oxoesters, thioesters, and amides), 1st establishing the sensitivity of each probe to an elec. field using vibrational Stark spectroscopy, vibrational solvatochromism, and mol. dynamics simulations, and then applying these results to re-interpret data already in the literature for enzymes such as 4-chlorobenzoyl-CoA dehalogenase and serine proteases such as chymotrypsin and subtilisin BPN' and Carlsberg. These results demonstrated that the vibrational Stark effect provides a general framework for estg. the electrostatic contribution to the catalytic rate and may provide a metric for the design or modification of enzymes. Opportunities and limitations of the approach are also described.
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  15. 15
    Tonge, P. J.; Carey, P. R. Length of the acyl carbonyl bond in acyl-serine proteases correlates with reactivity. Biochemistry 1990, 29, 10723– 10727,  DOI: 10.1021/bi00500a002
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    15
    Length of the acyl carbonyl bond in acyl-serine proteases correlates with reactivity
    Tonge, Peter J.; Carey, Paul R.
    Biochemistry (1990), 29 (48), 10723-7CODEN: BICHAW; ISSN:0006-2960.
    Resonance Raman (RR) spectroscopy was used to obtain the vibrational spectrum of the acyl carbonyl group in a series of acylchymotrypsins and acylsubtilisins at the pH of optimum hydrolysis. The acyl-enzymes, which utilized (arylacryloyl) acyl groups, included 3 oxyanion hole mutants of subtilisin BPN', Asn-155 → Leu, Asn-155 → Gln, and Asn-155 → Arg, and encompassed a 500-fold range of deacylation rate consts. For each acyl-enzyme, a RR carbonyl band was identified that arose from a population of carbonyl groups undergoing nucleophilic attack in the active site. As the deacylation rate (k3) increased through the series of acyl-enzymes, the carbonyl stretching band (νC:O) was obsd. to shift to lower frequency, indicating an increase in the single bond character of the reactive acyl carbonyl group. Expts. involving the oxyanion hole mutants of subtilisin BPN' indicated that a shift of νC:O to lower frequency resulted from stronger H-bonding of the acyl carbonyl group in the oxyanion hole. A plot of log k3 against νC:O was linear over the range investigated, demonstrating that the changes in νC:O correlated with the free energy of activation for the deacylation reaction. By use of an empirical correlation between carbonyl frequency (νC:O) and carbonyl bond length (rC:O), it was estd. that rC:O increased by 0.015 Å as the deacylation rate increased 500-fold through the series of acyl-enzymes. This change in rC:O was ∼7% of that expected for going from a formal C:O double bond in the acyl-enzyme to a formal C-O single bond in the tetrahedral intermediate for deacylation. The data also allowed estn. of the energy needed to extend the acyl carbonyl group along its axis as 950 kJ/mol/Å.
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  16. 16
    Tonge, P. J.; Carey, P. R. Forces, bond lengths, and reactivity: fundamental insight into the mechanism of enzyme catalysis. Biochemistry 1992, 31, 9122– 9125,  DOI: 10.1021/bi00153a002
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    16
    Forces, bond lengths, and reactivity: fundamental insight into the mechanism of enzyme catalysis
    Tonge, Peter J.; Carey, Paul R.
    Biochemistry (1992), 31 (38), 9122-5CODEN: BICHAW; ISSN:0006-2960.
    Comparison of spectroscopic, kinetic, and thermodn. data for a series of functioning acyl-serine proteases suggests that the obsd. variation in deacylation rates can be accounted for by changes in the properties of the acyl-enzyme's ground state. The acyl-enzyme's catalytically crucial acyl carbonyl group is probed by resonance Raman spectroscopy. Its spectral frequency is used to gauge both the carbonyl bond length and the strength of hydrogen bonding (originating from groups making up the oxyanion hole) to the carbonyl oxygen atom. As the deacylation rate increases 16,300-fold through the series, a shift in carbonyl frequency, νC=O, of -54 cm-1 corresponds to a carbonyl bond length increase of 0.025 Å. The decrease in νC=O is also consistent with an increase in hydrogen bond donor enthalpy of -27 kJ mol-1. Interestingly, this value resembles closely the decrease in activation energy for deacylation through the series, 24 kJ mol-1, demonstrating that the hydrogen bonds to the carbonyl oxygen atom can provide sufficient energy to account for the obsd. rate accelerations.
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  17. 17
    Tonge, P. J.; Fausto, R.; Carey, P. R. FTIR studies of hydrogen bonding between α,β-unsaturated esters and alcohols. J. Mol. Struct. 1996, 379, 135– 142,  DOI: 10.1016/0022-2860(95)09117-3
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    17
    FTIR studies of hydrogen bonding between α,β-unsaturated esters and alcohols
    Tonge, P. J.; Fausto, R.; Carey, P. R.
    Journal of Molecular Structure (1996), 379 (), 135-142CODEN: JMOSB4; ISSN:0022-2860. (Elsevier)
    The enthalpy (and entropy) of hydrogen bond formation has been measured between the ester carbonyl groups of the two α,β-unsatd. esters thienylacryloyl (TAOMe) and 5-methylthienylacryloyl (5MeTAOMe) Me ester and the hydrogen bond donors ethanol, phenol and 3,5-dichlorophenol in CCl4. For the esters, the hydrogen bonding strengths were measured by quantitating the amt. of bound and unbound donor, using the O-H stretching region, as a function of temp. and applying the van't Hoff equation. The decrease in νC:O of the ester carbonyl group upon hydrogen bond formation (ΔνC:O) has also been measured and correlated with the enthalpy of hydrogen bond formation. A linear correlation is obsd. between the enthalpy of hydrogen bond formation -ΔH and ΔνC:O, with -ΔH = 1.36ΔνC:O-16.1, where ΔH is measured in kJ mol-1 and Δν in cm-1. Comparison with data for other carbonyl acceptor compds. indicates that the carbonyl group of the above α,β-unsatd. esters is more readily polarized than the carbonyl group of satd. esters or ketones. The quant. relationship between -ΔH and ΔνC:O derived here has been used to det. the change in the enthalpy of hydrogen bond formation between substrate and enzyme groups in a series of acylserine proteases.
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  18. 18
    Latajka, Z.; Scheiner, S. Correlation between interaction energy and shift of the carbonyl stretching frequency. Chem. Phys. Lett. 1990, 174, 179– 184,  DOI: 10.1016/0009-2614(90)80103-K
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    18
    Correlation between interaction energy and shift of the carbonyl stretching frequency
    Latajka, Zdzislaw; Scheiner, Steve
    Chemical Physics Letters (1990), 174 (2), 179-84CODEN: CHPLBC; ISSN:0009-2614.
    The shift in the C = O stretching frequency of H2CO, when interacting with Na+, Mg2+, H+, H3O+,and H2O, fits a linear correlation with the computed interaction energy. The slope of this line is such that 1 kcal mol-1 in ΔE is assocd. with a frequency decrease of 2 cm-1.
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    Banyay, M.; Sarkar, M.; Gräslund, A. A library of IR bands of nucleic acids in solution. Biophys. Chem. 2003, 104, 477– 488,  DOI: 10.1016/S0301-4622(03)00035-8
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    19
    A library of IR bands of nucleic acids in solution
    Banyay, Martina; Sarkar, Munna; Graslund, Astrid
    Biophysical Chemistry (2003), 104 (2), 477-488CODEN: BICIAZ; ISSN:0301-4622. (Elsevier Science B.V.)
    A review. This review presents a compilation and discussion of IR bands characteristic of nucleic acids in various conformations. The entire spectral range 1800-800 cm-1 relevant for DNA/RNA in aq. soln. has been subdivided into four sections. Each section contains descriptions of bands appearing from group specific parts of nucleic acid structure, such as nucleobase, base-sugar, sugar-phosphate and sugar moiety. The approach allows comparisons of information obtained from one spectral region with another. The IR band library should facilitate detailed and unambiguous assignment of structural changes, ligand binding, etc. in nucleic acids from IR spectra. is aimed at highlighting specific features that are useful for following major changes in nucleic acid structures. also concerns some recent results, where IR spectroscopy has been used to obtain semi-quant. information on coexisting modes of sugar pucker in oligonucleotides.
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  20. 20
    Menssen, R. J.; Tokmakoff, A. Length-Dependent Melting Kinetics of Short DNA Oligonucleotides Using Temperature-Jump IR Spectroscopy. J. Phys. Chem. B 2019, 123, 756– 767,  DOI: 10.1021/acs.jpcb.8b09487
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    20
    Length-dependent melting kinetics of short DNA oligonucleotides using temperature-jump IR spectroscopy
    Menssen, Ryan J.; Tokmakoff, Andrei
    Journal of Physical Chemistry B (2019), 123 (4), 756-767CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    In this work, we utilized FTIR and temp.-jump (T-jump) IR spectroscopy to investigate the melting thermodn. and kinetics of a series of 5 DNA sequences ranging from 6 to 14 base pairs long. IR spectroscopy is well suited for the study of DNA because of its ability to distinguish base-specific information, and the nanosecond time resoln. of the T-jump app. can access the relevant range of kinetics. Eyring anal. of a 2-state model examd. both the activation enthalpy and entropy, providing new insights into the energetic driving forces and phys. processes behind the assocn. and dissocn. while also helping to clarify the commonly obsd. neg. activation energy. Global anal. of the thermodn. and kinetic data applying a linear dependence of activation barriers on oligo length provides a holistic result by producing reasonable agreement between our data and existing nearest-neighbor (NN) thermodn. parameters blending the exptl. results with established predictive models. By studying the trends in the thermodn. and kinetics as a function of length, this work demonstrated a direct correlation between the effects addnl. dinucleotides have on the kinetics and the NN parameters for those dinucleotides. This result further supports the development of a kinetic analog to the thermodn. NN parameters.
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  21. 21
    Ashwood, B.; Sanstead, P. J.; Dai, Q.; He, C.; Tokmakoff, A. 5-Carboxylcytosine and Cytosine Protonation Distinctly Alter the Stability and Dehybridization Dynamics of the DNA Duplex. J. Phys. Chem. B 2020, 124, 627– 640,  DOI: 10.1021/acs.jpcb.9b11510
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    21
    5-Carboxylcytosine and cytosine protonation distinctly alter the stability and dehybridization dynamics of the DNA duplex
    Ashwood, Brennan; Sanstead, Paul J.; Dai, Qing; He, Chuan; Tokmakoff, Andrei
    Journal of Physical Chemistry B (2020), 124 (4), 627-640CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Applications assocd. with nucleobase protonation events are grounded in their fundamental impact on DNA thermodn., structure, and hybridization dynamics. Of the canonical nucleobases, N3 protonation of cytosine (C) is the most widely utilized in both biol. and nanotechnol. Naturally occurring C derivs. that shift the N3 pKa introduce an addnl. level of tunability. The epigenetic nucleobase 5-carboxylcytosine (caC) presents a particularly interesting example since this deriv. forms Watson-Crick base pairs of similar stability and displays pH-dependent behavior over the same range as the canonical nucleobase. However, the titratable group in caC corresponds to the exocyclic carboxyl group rather than N3, and the implications of these divergent protonation events toward DNA hybridization thermodn., kinetics, and base pairing dynamics remain poorly understood. Here, we study the pH dependence of these phys. properties using model oligonucleotides contg. C and caC with FTIR and temp.-jump IR spectroscopy. We demonstrate that N3 protonation of C completely disrupts duplex stability, leading to large shifts in the duplex/single-strand equil., a redn. in the cooperativity of melting, and an acceleration in the rate of duplex dissocn. In contrast, while increasing 5-carboxyl protonation in caC-contg. duplexes induces an increase in base pair fluctuations, the DNA duplex can tolerate substantial protonation without significant perturbation to the duplex/single-strand equil. However, 5-carboxyl protonation has a large impact on hybridization kinetics by reducing the transition state free energy. Our thermodn. and kinetic anal. provides new insight on the impact of two divergent protonation mechanisms in naturally occurring nucleobases on the biophys. properties of DNA.
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    Wood, B. R. The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues. Chem. Soc. Rev. 2016, 45, 1980– 1998,  DOI: 10.1039/C5CS00511F
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    The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues
    Wood, Bayden R.
    Chemical Society Reviews (2016), 45 (7), 1980-1998CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
    Since Watson and Crick's historical papers on the structure and function of DNA based on Rosalind Franklin's and Maurice Wilkin's X-ray diffraction patterns tremendous scientific curiosity has been aroused by the unique and dynamic structure of the mol. of life. A-DNA and B-DNA represent different conformations of the DNA mol., which is stabilized by hydrogen interactions between base pairs, stacking interactions between neighboring bases and long-range intra- and inter-backbone forces. This review highlights the contribution Fourier transform IR (FTIR) spectroscopy has made to the understanding of DNA conformation in relation to hydration and its potential role in clin. diagnostics. The review will first begin by elucidating the main forms of DNA conformation found in nature and the general structures of the A, B and Z forms. This is followed by a detailed critique on IR spectroscopy applied to DNA conformation highlighting pivotal studies on isolated DNA, polynucleotides, nucleoprotein and nucleohistone complexes. A discussion on the potential of diagnosing cancer using FTIR spectroscopy based on the detection of DNA bands in cells and tissues will ensue, highlighting the recent studies investigating the conformation of DNA in hydrated and dehydrated cells. The method of hydration as a way to facilitate DNA conformational band assignment will be discussed and the conformational change to the A-form upon dehydration will be used to explain the reason for the apparent lack of FTIR DNA signals obsd. in fixed or air-dried cells and tissues. The advantages of investigating B-DNA in the hydrated state, as opposed to A-DNA in the dehydrated state, are exemplified in a series of studies that show: (1) improved quantification of DNA in cells; (2) improved discrimination and reproducibility of FTIR spectra recorded of cells progressing through the cell cycle; (3) insights into the biol. significance of A-DNA as evidenced by an interesting study on bacteria, which can survive desiccation and at the same time undergo the B-A-B transition. Finally, the importance of preserving the B-DNA conformation for the diagnosis of cancer is put forward as way to improve the sensitivity of this powerful technique.
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  23. 23
    Hithell, G.; Ramakers, L. A. I.; Burley, G. A.; Hunt, N. T. Applications of 2D-IR Spectroscopy to Probe the Structural Dynamics of DNA. In Frontiers and Advances in Molecular Spectroscopy, Laane, J., Ed.; Elsevier, 2018; Chapter 3, pp 77– 100.
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    Hithell, G.; Shaw, D. J.; Donaldson, P. M.; Greetham, G. M.; Towrie, M.; Burley, G. A.; Parker, A. W.; Hunt, N. T. Long-Range Vibrational Dynamics Are Directed by Watson–Crick Base Pairing in Duplex DNA. J. Phys. Chem. B 2016, 120, 4009– 4018,  DOI: 10.1021/acs.jpcb.6b02112
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    24
    Long-Range Vibrational Dynamics Are Directed by Watson-Crick Base Pairing in Duplex DNA
    Hithell, Gordon; Shaw, Daniel J.; Donaldson, Paul M.; Greetham, Gregory M.; Towrie, Michael; Burley, Glenn A.; Parker, Anthony W.; Hunt, Neil T.
    Journal of Physical Chemistry B (2016), 120 (17), 4009-4018CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Ultrafast two-dimensional IR (2D-IR) spectroscopy of a 15-mer A-T DNA duplex in soln. has revealed structure-dependent vibrational coupling and energy transfer processes linking bases with the sugar-phosphate backbone. Duplex melting induces significant changes in the positions of off-diagonal peaks linking carbonyl and ring-stretching vibrational modes of the adenine and thymine bases with vibrations of the phosphate group and phosphodiester linkage. These indicate that Watson-Crick hydrogen bonding and helix formation lead to a unique vibrational coupling arrangement of base vibrational modes with those of the phosphate unit. On the basis of observations from time-resolved 2D-IR data, we conclude that rapid energy transfer processes occur between base and backbone, mediated by addnl. modes located on the deoxyribose moiety within the same nucleotide. These relaxation dynamics are insensitive to duplex melting, showing that efficient intramol. energy relaxation to the solvent via the phosphate groups is the key to excess energy dissipation in both single- and double-stranded DNA.
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    Krummel, A. T.; Zanni, M. T. DNA Vibrational Coupling Revealed with Two-Dimensional Infrared Spectroscopy: Insight into Why Vibrational Spectroscopy Is Sensitive to DNA Structure. J. Phys. Chem. B 2006, 110, 13991– 14000,  DOI: 10.1021/jp062597w
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    25
    DNA Vibrational Coupling Revealed with Two-Dimensional Infrared Spectroscopy: Insight into Why Vibrational Spectroscopy Is Sensitive to DNA Structure
    Krummel, Amber T.; Zanni, Martin T.
    Journal of Physical Chemistry B (2006), 110 (28), 13991-14000CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    Two-dimensional IR (2D IR) spectroscopy was used to study the carbonyl vibrational modes of guanine and cytosine bases in A- and B-form DNA. Located between 1600 and 1700 cm-1, these modes are often used to monitor DNA secondary structure with traditional IR spectroscopies such as FTIR, but traditional spectroscopies lack the necessary observables to unravel the coupling mechanisms that make these modes sensitive to secondary structure. By using 2D IR spectroscopy and electronic structure calcns. on d(G5C5) and d(GC)8 model nucleic acids, the authors find that hydrogen-bonded guanine/cytosine base pairs are primarily electrostatically coupled and that the coupling between these modes can be modeled with a transition dipole d. approach. In comparison, electrostatics is insufficient to model stacked bases because of cooperative charge-sharing effects, but the coupling can be accurately calcd. using a finite difference method. The authors find that the coupling is very strong for both hydrogen-bonded and stacked base geometries, creating vibrational modes that extend both across the base pairs and along the lengths of the helixes. The authors' results provide a phys. basis for understanding how strong coupling gives rise to the empirically established relation between IR spectroscopy and DNA/RNA secondary structure.
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    Krummel, A. T.; Mukherjee, P.; Zanni, M. T. Inter and Intrastrand Vibrational Coupling in DNA Studied with Heterodyned 2D-IR Spectroscopy. J. Phys. Chem. B 2003, 107, 9165– 9169,  DOI: 10.1021/jp035473h
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    26
    Inter and intrastrand vibrational coupling in DNA studied with heterodyned 2D-IR spectroscopy
    Krummel, Amber T.; Mukherjee, Prabuddha; Zanni, Martin T.
    Journal of Physical Chemistry B (2003), 107 (35), 9165-9169CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
    Heterodyned 2D-IR, frequency resolved photon echo, and pump-probe spectroscopies were collected to study the couplings and anharmonicities of cytidine and guanosine bases in DNA. Cytidine and guanosine anharmonicities were measured to be 9 and 14 cm-1, resp. Strong cross-peaks were obsd. between the guanosine (G) and cytosine (C) carbonyl stretches in the 2D-IR spectra of the self-complementary oligonucleotide dG5C5 (5'-GGGGGCCCCC-3'). The spectra are interpreted in terms of inter- and intrastrand couplings between the carbonyl modes, and an excitonic Hamiltonian, based on transition dipole coupling, was used to fit the 2D-IR spectra. The accuracy of this model is discussed in light of obsd. couplings to the ring modes.
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  27. 27
    Zhang, X.-X.; Brantley, S. L.; Corcelli, S. A.; Tokmakoff, A. DNA minor-groove binder Hoechst 33258 destabilizes base-pairing adjacent to its binding site. Commun. Biol. 2020, 3, 525  DOI: 10.1038/s42003-020-01241-4
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    27
    DNA minor-groove binder Hoechst 33258 destabilizes base-pairing adjacent to its binding site
    Zhang, Xin-Xing; Brantley, Shelby L.; Corcelli, Steven A.; Tokmakoff, Andrei
    Communications Biology (2020), 3 (1), 525CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
    Understanding the dynamic interactions of ligands to DNA is important in DNA-based nanotechnologies. By structurally tracking the dissocn. of Hoechst 33258-bound DNA (d(CGCAAATTTGCG)2) complex (H-DNA) with T-jump 2D-IR spectroscopy, the ligand is found to strongly disturb the stability of the three C:G base pairs adjacent to A:T the binding site, with the broken base pairs being more than triple at 100 ns. The strong stabilization effect of the ligand on DNA duplex makes this observation quite striking, which dramatically increases the melting temp. and dissocn. time. MD simulations demonstrate an important role of hydration water and counter cations in maintaining the sepn. of terminal base pairs. The hydrogen bonds between the ligand and thymine carbonyls are crucial in stabilizing H-DNA, whose breaking signal appearing prior to the complete dissocn. Thermodn. anal. informs us that H-DNA assocn. is a concerted process, where H cooperates with DNA single strands in forming H-DNA.
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  28. 28
    Hithell, G.; Donaldson, P. M.; Greetham, G. M.; Towrie, M.; Parker, A. W.; Burley, G. A.; Hunt, N. T. Effect of oligomer length on vibrational coupling and energy relaxation in double-stranded DNA. Chem. Phys. 2018, 512, 154– 164,  DOI: 10.1016/j.chemphys.2017.12.010
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    28
    Effect of oligomer length on vibrational coupling and energy relaxation in double-stranded DNA
    Hithell, Gordon; Donaldson, Paul M.; Greetham, Gregory M.; Towrie, Michael; Parker, Anthony W.; Burley, Glenn A.; Hunt, Neil T.
    Chemical Physics (2018), 512 (), 154-164CODEN: CMPHC2; ISSN:0301-0104. (Elsevier B.V.)
    The effect of oligomer length on the vibrational mode coupling and energy relaxation mechanisms of AT-rich DNA oligomers in double- and single-stranded conformations has been investigated using two-dimensional IR (2D-IR) spectroscopy. Vibrational coupling of modes of the DNA bases to the sym. stretching vibration of the backbone phosphate group was obsd. for oligomers long enough to form duplex-DNA structures. The coupling was lost upon melting of the duplex. No significant effect of oligomer length or DNA secondary structure was found on either the timescale for vibrational relaxation of the base modes or the mechanism, which was consistent with a cascade process from base modes to intermediate modes, some of which are located on the deoxyribose group, and subsequently to the phosphate backbone. The study shows that vibrational coupling between base and backbone requires formation of the double-helix structure while vibrational energy management is an inherent property of the nucleotide.
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    Zhang, Y.; de La Harpe, K.; Beckstead, A. A.; Martínez-Fernández, L.; Improta, R.; Kohler, B. Excited-State Dynamics of DNA Duplexes with Different H-Bonding Motifs. J. Phys. Chem. Lett. 2016, 7, 950– 954,  DOI: 10.1021/acs.jpclett.6b00074
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    Excited-State Dynamics of DNA Duplexes with Different H-Bonding Motifs
    Zhang, Yuyuan; de La Harpe, Kimberly; Beckstead, Ashley A.; Martinez-Fernandez, Lara; Improta, Roberto; Kohler, Bern
    Journal of Physical Chemistry Letters (2016), 7 (6), 950-954CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
    The excited-state dynamics of three distinct forms of the d(GC)9·d(GC)9 DNA duplex were studied by combined time-resolved IR expts. and quantum mech. calcns. In the B- and Z-forms, bases on opposite strands form Watson-Crick (WC) base pairs but stack differently because of salt-induced changes in backbone conformation. At low pH, the two strands assoc. by Hoogsteen (HG) base pairing. UV-induced intrastrand electron transfer (ET) triggers interstrand proton transfer (PT) in the B- and Z-forms, but the PT pathway is blocked in the HG duplex. Despite the different decay mechanisms, a common excited-state lifetime of ∼30 ps is obsd. in all three duplex forms. The ET-PT pathway in the WC duplexes and the solely intrastrand ET pathway in the HG duplex yield the same pair of π-stacked radicals on one strand. Back ET between these radicals is proposed to be the rate-limiting step behind excited-state deactivation in all three duplexes.
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  30. 30
    Schreier, W. J.; Schrader, T. E.; Koller, F. O.; Gilch, P.; Crespo-Hernández, C. E.; Swaminathan, V. N.; Carell, T.; Zinth, W.; Kohler, B. Thymine Dimerization in DNA Is an Ultrafast Photoreaction. Science 2007, 315, 625,  DOI: 10.1126/science.1135428
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    Thymine Dimerization in DNA Is an Ultrafast Photoreaction
    Schreier, Wolfgang J.; Schrader, Tobias E.; Koller, Florian O.; Gilch, Peter; Crespo-Hernandez, Carlos E.; Swaminathan, Vijay N.; Carell, Thomas; Zinth, Wolfgang; Kohler, Bern
    Science (Washington, DC, United States) (2007), 315 (5812), 625-629CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Femtosecond time-resolved IR spectroscopy was used to study the formation of cyclobutane dimers in the all-thymine oligodeoxynucleotide (dT)18 by UV light at 272 nm. The appearance of marker bands in the time-resolved spectra indicates that the dimers are fully formed ∼1 ps after UV excitation. The ultrafast appearance of this mutagenic photolesion points to an excited-state reaction that is approx. barrierless for bases that are properly oriented at the instant of light absorption. The low quantum yield of this photoreaction is proposed to result from infrequent conformational states in the unexcited polymer, revealing a strong link between conformation before light absorption and photodamage.
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    Middleton, C. T.; de La Harpe, K.; Su, C.; Law, Y. K.; Crespo-Hernández, C. E.; Kohler, B. DNA Excited-State Dynamics: From Single Bases to the Double Helix. Annu. Rev. Phys. Chem. 2009, 60, 217– 239,  DOI: 10.1146/annurev.physchem.59.032607.093719
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    DNA excited-state dynamics: from single bases to the double helix
    Middleton, Chris T.; de La Harpe, Kimberly; Su, Charlene; Law, Yu Kay; Crespo-Hernandez, Carlos E.; Kohler, Bern
    Annual Review of Physical Chemistry (2009), 60 (), 217-239CODEN: ARPLAP; ISSN:0066-426X. (Annual Reviews Inc.)
    A review. UV light is strongly absorbed by DNA, producing excited electronic states that sometimes initiate damaging photochem. reactions. Fully mapping the reactive and nonreactive decay pathways available to excited electronic states in DNA is a decades-old quest. Progress toward this goal has accelerated rapidly in recent years, in large measure because of ultrafast laser expts. Here we review recent discoveries and controversies concerning the nature and dynamics of excited states in DNA model systems in soln. Nonradiative decay by single, solvated nucleotides occurs primarily on the subpicosecond timescale. Surprisingly, excess electronic energy relaxes one or two orders of magnitude more slowly in DNA oligo- and polynucleotides. Highly efficient nonradiative decay pathways guarantee that most excited states do not lead to deleterious reactions but instead relax back to the electronic ground state. Understanding how the spatial organization of the bases controls the relaxation of excess electronic energy in the double helix and in alternative structures is currently one of the most exciting challenges in the field.
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    Torres, J.; Kukol, A.; Goodman, J. M.; Arkin, I. T. Site-specific examination of secondary structure and orientation determination in membrane proteins: The peptidic 13C═18O group as a novel infrared probe. Biopolymers 2001, 59, 396– 401,  DOI: 10.1002/1097-0282(200111)59:6<396::AID-BIP1044>3.0.CO;2-Y
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    Site-specific examination of secondary structure and orientation determination in membrane proteins: the peptidic 13C=18O group as a novel infrared probe
    Torres, Jaume; Kukol, Andreas; Goodman, Jonathan M.; Arkin, Isaiah T.
    Biopolymers (2001), 59 (6), 396-401CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
    Detailed site-specific information can be exceptionally useful in structural studies of macromols. in general and proteins in particular. Such information is usually obtained from spectroscopic studies using a label/probe that can reflect on particular properties of the protein. A suitable probe must not modify the native properties of the protein, and should yield interpretable structural information, as is the case with isotopic labels used by Fourier transform IR (FTIR) spectroscopy. In particular, 1-13C=O labels have been shown to relay site-specific secondary structure and orientational information, although limited to small peptides. The reason for this limitation is the high natural abundance of 13C and the lack of baseline resoln. between the main amide I band and the isotope-edited peak. Herein, we dramatically extend the utility of isotope edited FTIR spectroscopy to proteins of virtually any size through the use of a new 1-13C=18O label. The double-isotope label virtually eliminates any contribution from natural abundance 13C. More importantly, the isotope-edited peak is further red-shifted (in accordance with ab initio Hartree-Fock calcns.) and is now completely baseline resolved from the main amide I band. Taken together, this new label enables detn. of site specific secondary structure and orientation in proteins of virtually any size. Even in small peptides 1-13C=18O is far preferable as a label in comparison to 1-13C=16O since it enables anal. without the need for any deconvolution or peak fitting procedures. Finally, the results obtained herein represent the first stage in the application of site-directed dichroism to the structural elucidation of polytopic membrane proteins.
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    Decatur, S. M. Elucidation of Residue-Level Structure and Dynamics of Polypeptides via Isotope-Edited Infrared Spectroscopy. Acc. Chem. Res. 2006, 39, 169– 175,  DOI: 10.1021/ar050135f
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    Elucidation of Residue-Level Structure and Dynamics of Polypeptides via Isotope-Edited Infrared Spectroscopy
    Decatur, Sean M.
    Accounts of Chemical Research (2006), 39 (3), 169-175CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. IR spectroscopy is a powerful tool for analyzing the structure of proteins and peptides. The amide I band is particularly sensitive to the strength and position of the hydrogen bonds that define secondary structure as well as dipole-dipole interactions that are affected by the geometry of the peptide backbone. The introduction of a single 13C-labeled carbonyl into a peptide backbone results in a resolvable shoulder to the main amide I band, which can be analyzed as a sep. peak. Thus, site-specific structural information can be obtained by sequential, systematic labeling of the backbone. This method of isotope-edited IR spectroscopy is a tool for obtaining medium-resoln. information about the backbone conformation and dynamics. This tool has been used to dissect the conformation and dynamics of α helixes and amyloid aggregates, where the versatility of possible sampling with IR spectroscopy is well-suited for studies of large-protein aggregates.
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    Brielle, E. S.; Arkin, I. T. Quantitative Analysis of Multiplex H-Bonds. J. Am. Chem. Soc. 2020, 142, 14150– 14157,  DOI: 10.1021/jacs.0c04357
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    Quantitative Analysis of Multiplex H-Bonds
    Brielle, Esther S.; Arkin, Isaiah T.
    Journal of the American Chemical Society (2020), 142 (33), 14150-14157CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    H-bonding is the predominant geometrical determinant of biomol. structure and interactions. As such, considerable analyses have been undertaken to study its detailed energetics. The focus, however, has been mostly reserved for H-bonds comprising a single donor and a single acceptor. Herein, we measure the prevalence and energetics of multiplex H-bonds that are formed between three or more groups. We show that 92% of all transmembrane helixes have at least one non-canonical H-bond formed by a serine or threonine residue whose hydroxyl side chain H-bonds to an over-coordinated carbonyl oxygen at position i-4, i-3, or i in the sequence. Isotope-edited FTIR spectroscopy, coupled with DFT calcns., enables us to det. the bond enthalpies, pointing to values that are up to 127% higher than that of a single canonical H-bond. We propose that these strong H-bonds serve to stabilize serine and threonine residues in hydrophobic environments while concomitantly providing them flexibility between different configurations, which may be necessary for function.
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    Scheerer, D.; Chi, H.; McElheny, D.; Keiderling, T. A.; Hauser, K. Isotopically Site-Selected Dynamics of a Three-Stranded β-Sheet Peptide Detected with Temperature-Jump Infrared-Spectroscopy. J. Phys. Chem. B 2018, 122, 10445– 10454,  DOI: 10.1021/acs.jpcb.8b08336
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    Isotopically Site-Selected Dynamics of a Three-Stranded β-Sheet Peptide Detected with Temperature-Jump Infrared-Spectroscopy
    Scheerer, David; Chi, Heng; McElheny, Dan; Keiderling, Timothy A.; Hauser, Karin
    Journal of Physical Chemistry B (2018), 122 (46), 10445-10454CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    IR detected temp.-jump (T-jump) spectroscopy and site-specific isotopic labeling were applied to study a model three-stranded β-sheet peptide with the goal of individually probing the dynamics of strand and turn structural elements. This peptide had two DPro-Gly (pG) turn sequences to stabilize the two component hairpins, which were labeled with 13C=O on each of the Gly residues to resolve them spectroscopically. Labeling the second turn on the amide preceding the DPro (Xxx-DPro amide) provided an alternate turn label as a control. Placing 13C=O labels on specific in-strand residues gave shifted modes that overlap the Xxx-DPro amide I' modes. Their impact could be sepd. from the turn dynamics by a novel difference transient anal. approach. Fourier-transform IR spectra were modeled with d. functional theory-computations which showed the local, isotope-selected vibrations were effectively uncoupled from the other amide I modes. Our T-jump dynamics results, combined with NMR structures and equil. spectral measurements, showed the first turn to be most stable and best formed with the slowest dynamics, whereas the second turn and first strand (N-terminus) had similar dynamics, and the third strand (C-terminus) had the fastest dynamics and was the least structured. The relative dynamics of the strands, Xxx-DPro amides, and 13C-labeled Gly residues on the turns also qual. corresponded to mol. dynamics (MD) simulations of turn and strand fluctuations. MD trajectories indicated the turns to be bistable, with the first turn being Type I' and the second turn flipping from I' to II'. The differences in relaxation times for each turn and the sep. strands revealed that the folding process of this turn-stabilized β-sheet structure proceeds in a multistep process.
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  36. 36
    Setnička, V.; Huang, R.; Thomas, C. L.; Etienne, M. A.; Kubelka, J.; Hammer, R. P.; Keiderling, T. A. IR Study of Cross-Strand Coupling in a β-Hairpin Peptide Using Isotopic Labels. J. Am. Chem. Soc. 2005, 127, 4992– 4993,  DOI: 10.1021/ja043007f
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    IR Study of Cross-Strand Coupling in a β-Hairpin Peptide Using Isotopic Labels
    Setnicka, Vladimir; Huang, Rong; Thomas, Catherine L.; Etienne, Marcus A.; Kubelka, Jan; Hammer, Robert P.; Keiderling, Timothy A.
    Journal of the American Chemical Society (2005), 127 (14), 4992-4993CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Model β-hairpin peptides can be used to develop understanding of fundamental elements of β-sheet secondary structure formation and stability. The authors have studied two 13C-labeled variants of a β-hairpin peptide modified from a design originally proposed by S. H. Gellman: Arg-Tyr-Val-Glu-Val-Aib-Gly-Lys-Lys-Ile-Leu-Gln. In this peptide, the Aib-Gly residues form a β-turn, while 13C-labels are on the amide C:O of Val-3, Lys-8 in HBG-L and Val-3, Ile-10 in HBG-S. Both these peptides are labeled on opposite strands of the hairpin, but differ in the labeling pattern. One (HBG-L) forms a large (14-atom) H-bonded ring of labeled C:Os, while the other (HBG-S) forms a small (10-atom) H-bonded ring. These impact the amide I IR spectra, with HBG-L having a 13C frequency and intensity higher than that of HBG-S, in good agreement with the authors' spectral simulations based on quantum mech. derived force fields. The thermal behavior of both peptides yields a broad thermal transition and lacks an isosbestic point. The 13C band for HBG-L has the largest intensity change with temp., distinct from the 12C change and the HBG-S 13C change.
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  37. 37
    Barber-Armstrong, W.; Donaldson, T.; Wijesooriya, H.; Silva, R. A. G. D.; Decatur, S. M. Empirical Relationships between Isotope-Edited IR Spectra and Helix Geometry in Model Peptides. J. Am. Chem. Soc. 2004, 126, 2339– 2345,  DOI: 10.1021/ja037863n
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    37
    Empirical Relationships between Isotope-Edited IR Spectra and Helix Geometry in Model Peptides
    Barber-Armstrong, Wendy; Donaldson, Teraya; Wijesooriya, Himali; Silva, R. A. Gangani D.; Decatur, Sean M.
    Journal of the American Chemical Society (2004), 126 (8), 2339-2345CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    IR spectroscopy (IR) is commonly used to study secondary structure of both peptides and proteins. The amide I band is very sensitive to peptide secondary structure, and the conformation of a peptide can be probed at the residue level by introducing site-specific isotope-labels into the peptide backbone. The replacement of a carbonyl 12C with a 13C results in a ∼40 cm-1 shift in the amide I' band. The amide I bands of specifically labeled helixes should vary systematically as a function of the no. and relative spacing of the labeled residues; thus one should be able to describe the conformation of a polypeptide in substantial detail by probing the changes in IR spectra as a function of the no. and positioning of isotope labels. In this study, we report IR spectra of a series of differently labeled helical peptides. A series of 25mer peptides were synthesized based on the repeat sequence (AAAAK)n. We have varied the no. and spacing of the labels on each peptide and studied the changes in the 12C and 13C amide I' band due to label position. Our results indicate that changing the no. of labels changes the frequency and intensity of both the 12C and the 13C amide mode. We also found that varying the spacing between labels causes these amide peaks to shift. Isotope labeling, combined with IR spectroscopy and theor. predictions, may generate a description of peptide backbone conformations at the residue level.
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  38. 38
    Decatur, S. M.; Antonic, J. Isotope-edited infrared spectroscopy of helical peptides. J. Am. Chem. Soc. 1999, 121, 11914– 11915,  DOI: 10.1021/ja991279q
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    38
    Isotope-Edited Infrared Spectroscopy of Helical Peptides
    Decatur, Sean M.; Antonic, Jelena
    Journal of the American Chemical Society (1999), 121 (50), 11914-11915CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Short polypeptides which form stable a helixes in aq. soln. are classic models for studying the factors which contribute to helix stability as well as the mechanism of helix formation. The most common tool for characterizing helix content in these peptides is far-UV CD; however, CD spectra can only give information about the overall helix content of a peptide, not the residue-level distribution of helix content within a peptide. Yet, residue-level information is essential to understanding important questions about helix formation and helix stability, such as the characterization and quantification of end-fraying effects and the impact of end-capping interactions. We report that isotope-edited IR spectroscopy opens a new window for observing conformation of specific residues in model helical peptides. IR is a powerful tool for probing the secondary structure of polypeptides in the steady state, and transient IR absorption has been used to observe the kinetics of protein dynamics during folding/unfolding and functional events. The primary spectral feature used in these studies is the amide I' mode. Due to transition dipole coupling between peptide moieties, the amide I' mode is very sensitive to the backbone geometry of a polypeptide, and the frequency and intensity of this band are sensitive to protein secondary structure. However, while a conventional Fourier transform IR (FTIR) spectrum gives information about the overall secondary structure content of the polypeptide, it cannot be used to det. conformations of specific local residues, and thus it is no more useful than CD for studying problems such as end-fraying. One approach to increasing the information content of FTIR spectra is to introduce 13C labels into the peptide backbone. Labeling of backbone carbonyls with 13C results in ∼37 cm-1 shift of the amide I' mode, sepg. the amide I' band of 13C-labeled residues from that of the 12C band. Isotope-edited FTIR has been used to probe the structures of particular regions within a protein and to observe conformational changes involved in protein-protein interactions. We have applied isotope-edited FTIR to probe structural details of an alanine-rich α helical peptide. A series of peptides (L1-L4) were synthesized in which two residues of 1-13C-alanine were incorporated into the sequence.
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  39. 39
    Deng, H.; Vedad, J.; Desamero, R. Z. B.; Callender, R. Difference FTIR Studies of Substrate Distribution in Triosephosphate Isomerase. J. Phys. Chem. B 2017, 121, 10036– 10045,  DOI: 10.1021/acs.jpcb.7b08114
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    39
    Difference FTIR Studies of Substrate Distribution in Triosephosphate Isomerase
    Deng, Hua; Vedad, Jayson; Desamero, Ruel Z. B.; Callender, Robert
    Journal of Physical Chemistry B (2017), 121 (43), 10036-10045CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Triosephosphate isomerase (TIM) catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (GAP), via an enediol(ate) intermediate. The detn. of substrate population distribution in the TIM/substrate reaction mixt. at equil., as well as characterization of the substrate-enzyme interactions in the Michaelis complex are on-going efforts toward the understanding of TIM reaction mechanism. Here, by using isotope-edited difference FITR studies with unlabeled and 13C labeled substrate at specific C atoms, we were able to show that in the reaction mixt. at equil., that the keto substate DHAP was the dominate species and the populations of the aldehyde substrate GAP and intermediate enediol(ate) were very low, consistent with the results from previous X-ray structural and 13C NMR studies. Furthermore, within the DHAP side of the Michaelis complex, there was a set of conformational sub-states that could be characterized by the different C2:O stretch frequencies. The C2:O frequency differences reflected the different degree of the C2:O bond polarization due to H-bonding from active site residues. The C2:O bond polarization has been considered as an important component for the substrate activation within Michaelis complex. We found that in enzyme-substrate reaction mixt. with TIM from different organisms, the no. of sub-states and their population distribution within the DHAP side of the Michaelis complex may be different. These discoveries provide a rare opportunity to probe the interconversion dynamics of these DHAP sub-states, and form the bases in the future studies to det. if the TIM-catalyzed reaction follows a simple linear reaction pathway as previously believed or follows parallel reaction pathways as suggested in another enzyme system that also shows a set of sub-states in the Michaelis complex.
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  40. 40
    Tonge, P. J.; Carey, P. R. Direct observation of the titration of substrate carbonyl groups in the active site of alpha-chymotrypsin by resonance Raman spectroscopy. Biochemistry 1989, 28, 6701,  DOI: 10.1021/bi00442a025
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    Direct observation of the titration of substrate carbonyl groups in the active site of α-chymotrypsin by resonance Raman spectroscopy
    Tonge, Peter J.; Carey, Paul R.
    Biochemistry (1989), 28 (16), 6701-9CODEN: BICHAW; ISSN:0006-2960.
    By use of resonance Raman (RR) spectroscopy, the population of the reactive carbonyl group in active acyl-chymotrypsins was characterized and correlated with acyl-enzyme reactivity. RR spectra were obtained, with a flow system and 324- and 337.5-nm excitation, at low and active pH for 6 acyl-chymotrypsins, viz., (indoleacryloyl)-, (4-amino-3-nitrocinnamoyl)-, (furylacryloyl)-, [(5-ethylfuryl)acryloyl]-, (thienylacryloyl)-, and [(5-methylthienyl)acryloyl]-chymotrypsin. These acyl-enzymes represented a 100-fold range of deacylation rate consts. Good RR spectral quality enabled the vibrational spectrum of the carbonyl group at low and active pH in each acyl-enzyme to be obtained. The measured pKa of the spectroscopic changes in the carbonyl region was identical with that for the deacylation kinetics, showing that the RR carbonyl features reflect the ionization state of histidine-57. A carbonyl population was obsd. in the active acyl-enzymes in which the carbonyl O atom of the reactive acyl linkage was H-bonded in the active site. The proportion of this H population, with respect to other obsd. non-H-bonded species, together with the degree of polarization of the carbonyl bond, as monitored by νC:O, was correlated with the deacylation rate consts. of the acyl-enzymes. It was proposed that the H-bonded carbonyl species is located at or near the oxyanion hole and represents the ground state from which deacylation occurs. An increase in the proportion of the H-bonded population and an increase in polarization of the carbonyl bond result in an increase in deacylation rate const. Thus, for the 1st time direct RR data are available on the catalytically transformed region which relate to the difference in acyl-enzyme reactivity.
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  41. 41
    Price, D. A.; Kartje, Z. J.; Hughes, J. A.; Hill, T. D.; Loth, T. M.; Watts, J. K.; Gagnon, K. T.; Moran, S. D. Infrared Spectroscopy Reveals the Preferred Motif Size and Local Disorder in Parallel Stranded DNA G-Quadruplexes. ChemBioChem 2020, 19, 2792– 2804,  DOI: 10.1002/cbic.202000136
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    Toyama, A.; Fujimoto, N.; Hanada, N.; Ono, J.; Yoshimitsu, E.; Matsubuchi, A.; Takeuchi, H. Assignments and hydrogen bond sensitivities of UV resonance Raman bands of the C8-deuterated guanine ring. J. Raman Spectrosc. 2002, 33, 699– 708,  DOI: 10.1002/jrs.899
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    42
    Assignments and hydrogen bond sensitivities of UV resonance Raman bands of the C8-deuterated guanine ring
    Toyama, Akira; Fujimoto, Naoko; Hanada, Naoki; Ono, Junko; Yoshimitsu, Emiko; Matsubuchi, Akiko; Takeuchi, Hideo
    Journal of Raman Spectroscopy (2002), 33 (9), 699-708CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    Isotope-edited Raman spectroscopy, a combination of site-selective isotopic labeling and Raman difference spectroscopy, is a useful method for studying the structure and interaction of individual nucleic acid residues in oligonucleotides. To obtain basic data for applying isotope-edited Raman spectroscopy to guanine residues, the authors studied the vibrational modes of UV resonance Raman bands of the C8-deuterated guanine ring by examg. the wavenumber shifts upon seven isotopic substitutions (2-13C, 2-15N, 6-18O, 7-15N, 8-13C, 9-15N and 1'-13C). The H bond sensitivities of the Raman bands were also studied by comparing the Raman spectra recorded in several solvents of different H bonding properties. Some of the Raman bands are markers of H bonding at specific donor or acceptor sites on the guanine ring. The Raman bands, which shift on C8-deuteration, remain in the difference spectrum between the unlabeled and C8-deuterated guanine rings. Among them, a neg. peak around 1525 cm-1 and a strong pos./neg. peak pair around 1485/1465 cm-1 serve as markers of H bonding at N7 and C6=O, resp. Another weak pos./neg. peak pair around 1025/1040 cm-1 is sensitive to H bonding at the proton donor sites (N1 - H and N2 - H2). The applicability of the H bond markers was tested by using a 22-mer oligonucleotide duplex contg. eight guanine residues and its analog in which a single guanine residue is C8-deuterated. The difference spectrum shows that the H bonding state of the guanine residue at the labeled position is consistent with the Watson-Crick base pair structure of DNA. Isotope-edited Raman spectroscopy is a useful tool for studying the H bonding state of selected guanine residues in oligonucleotides.
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  43. 43
    Toyama, A.; Matsubuchi, A.; Fujimoto, N.; Takeuchi, H. Isotope-edited UV Raman spectroscopy of protein–DNA interactions: binding modes of cyclic AMP receptor protein to a natural DNA recognition site. J. Raman Spectrosc. 2005, 36, 300– 306,  DOI: 10.1002/jrs.1289
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    43
    Isotope-edited UV Raman spectroscopy of protein-DNA interactions: binding modes of cyclic AMP receptor protein to a natural DNA recognition site
    Toyama, Akira; Matsubuchi, Akiko; Fujimoto, Naoko; Takeuchi, Hideo
    Journal of Raman Spectroscopy (2005), 36 (4), 300-306CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    Isotope-edited UV Raman spectroscopy was applied to the study of the binding mode of cAMP (cAMP) receptor protein (CRP) to a 22-mer oligonucleotide (LacDNA) representing the primary CRP binding site of the E. coli lac promoter. LacDNA contains four guanine residues in the consensus pentamer regions (G5 and G7 on the sense strand and G5' and G7' on the anti-sense strand) and they were individually labeled with deuterium at C(8) on the guanine ring. In the UV (251 nm) Raman difference spectrum between unlabeled and C(8)-D-labeled LacDNA, a sharp pos./neg. peak pair appeared at ,-1490/1465 cm-1, which was assigned to a guanine ring vibration (ν6/ν6') sensitive to the hydrogen bonding state at C(6)=O. CRP is a dimeric protein and forms two complexes with the cofactor cAMP, i.e. half-filled CRP-(cAMP), and fully liganded CRP-(cAMP)2. The ν6/ν6' wavenumbers measured in the presence of CRP showed that CRP-(cAMP)1 binds to G5 and G5' in a sym. manner, whereas CRP-(cAMP)2 exhibits an addnl. binding to G7. Since the base sequence of LacDNA and the structure of CRP-(cAMP)1 are both asym., the sym. LacDNA-CRP-(cAMP)1 interaction suggests that CRP-(cAMP)1, which is considered to be dominant under physiol. conditions, has a conformational flexibility to conform to structural asymmetry of natural DNA sequences. In contrast, the sym. complex CRP-(cAMP)2 binds to LacDNA asym., suggesting a decreased flexibility of CRP in the fully liganded form. Isotope-edited UV Raman spectroscopy provides unique information on the DNA recognition by CRP.
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  44. 44
    Chen, Y.; Eldho, N. V.; Dayie, T. K.; Carey, P. R. Probing Adenine Rings and Backbone Linkages Using Base Specific Isotope-Edited Raman Spectroscopy: Application to Group II Intron Ribozyme Domain V. Biochemistry 2010, 49, 3427– 3435,  DOI: 10.1021/bi902117w
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    44
    Probing Adenine Rings and Backbone Linkages Using Base Specific Isotope-Edited Raman Spectroscopy: Application to Group II Intron Ribozyme Domain V
    Chen, Yuanyuan; Eldho, Nadukkudy V.; Dayie, T. Kwaku; Carey, Paul R.
    Biochemistry (2010), 49 (16), 3427-3435CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    Raman difference spectroscopy is used to probe the properties of a 36-nt RNA mol., "D5", which lies at the heart of the catalytic app. in group II introns. For D5 that has all of its adenine residues labeled with 13C and 15N and utilizing Raman difference spectroscopy, we identify the conformationally sensitive -C-O-P-O-C- stretching modes of the unlabeled bonds adjacent to adenine bases, as well as the adenine ring modes themselves. The phosphodiester modes can be assigned to individual adenine residues based on earlier NMR data. The effect of Mg2+ binding was explored by analyzing the Raman difference spectra for [D5 + Mg2+] minus [D5 no Mg2+], for D5 unlabeled, or D5 labeled with 13C/15N-enriched adenine. In both sets of data we assign differential features to G ring modes perturbed by Mg2+ binding at the N7 position. In the A-labeled spectra we attribute a Raman differential near 1450 cm-1 and changes of intensity at 1296 cm-1 to Mg binding at the N7 position of adenine bases. The A and G bases involved in Mg2+ binding again can be identified using earlier NMR results. For the unlabeled D5, a change in the C-O-P-O-C stretch profile at 811 cm-1 upon magnesium binding is due to a "tightening up" (in the sense of a more rigid mol. with less dynamic interchange among competing ribose conformers) of the D5 structure. For adenine-labeled D5, small changes in the adenine backbone bond signatures in the 810-830 cm-1 region suggest that small conformational changes occur in the tetraloop and bulge regions upon binding of Mg2+. The PO2- stretching vibration, near 1100 cm-1, from the nonbridging phosphate groups, probes the effect of Mg2+-hydrate inner-sphere interactions that cause an upshift. In turn, the upshift is modulated by the presence of monovalent cations since in the presence of Na+ and Li+ the upshift is 23 cm-1 while in the presence of K+ and Cs+ it is 13 cm-1, a finding that correlates with the differences in hydration radii. These subtle differences in electrostatic interactions may be related to obsd. variations in catalytic activity. For a reconstructed ribozyme comprising domains 1-3 (D123) connected in cis plus domain 5 (D5) supplied in trans, cleavage of spliced exon substrates in the presence of magnesium and K+ or Cs+ is more efficient than that in the presence of magnesium with Na+ or Li+.
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  45. 45
    Antonopoulos, I. H.; Warner, B. A.; Carey, P. R. Concerted Protein and Nucleic Acid Conformational Changes Observed Prior to Nucleotide Incorporation in a Bacterial RNA Polymerase: Raman Crystallographic Evidence. Biochemistry 2015, 54, 5297– 5305,  DOI: 10.1021/acs.biochem.5b00484
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    45
    Concerted Protein and Nucleic Acid Conformational Changes Observed Prior to Nucleotide Incorporation in a Bacterial RNA Polymerase: Raman Crystallographic Evidence
    Antonopoulos, Ioanna H.; Warner, Brittany A.; Carey, Paul R.
    Biochemistry (2015), 54 (34), 5297-5305CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    Transcription elongation requires the continuous incorporation of ribonucleotide triphosphates into a growing transcript. RNA polymerases (RNAPs) are able to processively synthesize a growing RNA chain via translocation of the RNAP enzyme along its nucleic acid template strand after each nucleotide addn. cycle. In this work, a time-resolved Raman spectroscopic anal. of nucleotide addn. in single crystals of the Thermus thermophilus elongation complex (TthEC) is reported. When [13C,15N]GTP (*GTP) is soaked into crystals of the TthEC, large reversible changes in the Raman spectrum that are assigned to protein and nucleic acid conformational events during a single-nucleotide incorporation are obsd. The *GTP population in the TthEC crystal reaches a stable population at 37 min, while substantial and reversible protein conformational changes (mainly ascribed to changes in α-helical Raman features) maximize at approx. 50 min. At the same time, changes in nucleic acid bases and phosphodiester backbone Raman marker bands occur. Catalysis begins at approx. 65-70 min, soon after the maximal protein and DNA changes, and is monitored via the decline in a triphosphate vibrational Raman mode from *GTP. The Raman data indicate that approx. 40% of the total triphosphate population, present as *GTP, reacts in the crystal. This may suggest that a second population of noncovalently bound *GTP resides in a site distinct from the catalytic site. The data reported here are an extension of our recent work on the elongation complex (EC) of a bacterial RNAP, Thermus thermophilus (Tth), where Raman spectroscopy and polyacrylamide gel electrophoresis were employed to monitor incorporation and misincorporation in single TthEC crystals. Therefore, the initial study establishes the groundwork for this study. In contrast to our previous study, in which incorporation takes place very rapidly inside the crystals, the data on this single crystal exhibit a slower time regime, which allows the dissection of the structural dynamics assocd. with GMP incorporation within the TthEC crystal.
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  46. 46
    Antonopoulos, I. H.; Murayama, Y.; Warner, B. A.; Sekine, S.-i.; Yokoyama, S.; Carey, P. R. Time-Resolved Raman and Polyacrylamide Gel Electrophoresis Observations of Nucleotide Incorporation and Misincorporation in RNA within a Bacterial RNA Polymerase Crystal. Biochemistry 2015, 54, 652– 665,  DOI: 10.1021/bi501166r
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    46
    Time-Resolved Raman and Polyacrylamide Gel Electrophoresis Observations of Nucleotide Incorporation and Misincorporation in RNA within a Bacterial RNA Polymerase Crystal
    Antonopoulos, Ioanna H.; Murayama, Yuko; Warner, Brittany A.; Sekine, Shun-ichi; Yokoyama, Shigeyuki; Carey, Paul R.
    Biochemistry (2015), 54 (3), 652-665CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    The bacterial RNA polymerase (RNAP) elongation complex (EC) is highly stable and is able to extend an RNA chain for thousands of nucleotides. Understanding the processive mechanism of nucleotide addn. requires detailed structural and temporal data for the EC reaction. Here, a time-resolved Raman spectroscopic anal. is combined with PAGE to monitor nucleotide addn. in single crystals of the Thermus thermophilus EC (TthEC) RNAP. When the cognate base GTP, labeled with 13C and 15N (*GTP), is soaked into crystals of the TthEC, changes in the Raman spectra show evidence of nucleotide incorporation and product formation. The major change is the redn. of *GTP's triphosphate intensity. Nucleotide incorporation is confirmed by PAGE assays. Both Raman and PAGE methods have a time resoln. of minutes. There is also Raman spectroscopic evidence of a second population of *GTP in the crystal that does not become covalently linked to the nascent RNA chain. When this population is removed by "soaking out" (placing the crystal in a soln. that contains no NTP), there are no perturbations to the Raman difference spectra, indicating that conformational changes are not detected in the EC. In contrast, the misincorporation of the noncognate base, 13C- and 15N-labeled UTP (*UTP), gives rise to large spectroscopic changes. As in the GTP expt., redn. of the triphosphate relative intensity in the Raman soak-in data shows that the incorporation reaction occurs during the first few minutes of our instrumental dead time. This is also confirmed by PAGE anal. Whereas PAGE data show *GTP converts 100% of the nascent RNA 14mer to 15mer, the noncognate *UTP converts only ∼50%. During *UTP soak-in, there is a slow, reversible formation of an α-helical amide I band in the Raman difference spectra peaking at 40 min. Similar to *GTP soak-in, *UTP soak-in shows Raman spectroscopic evidence of a second noncovalently bound *UTP population in the crystal. Moreover, the second population has a marked effect on the complex's conformational states because removing it by "soaking-out" unreacted *UTP causes large changes in protein and nucleic acid Raman marker bands in the time range of 10-100 min. The conformational changes obsd. for noncognate *UTP may indicate that the enzyme is prepg. for proofreading to excise the misincorporated base. This idea is supported by the PAGE results for *UTP soak-out that show endonuclease activity is occurring.
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    Hoogsteen, K. The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine. Acta Crystallogr. 1963, 16, 907– 916,  DOI: 10.1107/S0365110X63002437
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    The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine
    Hoogsteen, Karst
    Acta Crystallographica (1963), 16 (9), 907-16CODEN: ACCRA9; ISSN:0365-110X.
    Crystals of a 1:1 H-bonded complex between 1-methylthymine and 9-methyladenine can be grown from an aq. soln. contg. equimol. quantities of the 2 compds. The crystals are monoclinic, with a 8.304, b 6.552, c 12.837 A. and β = 106° 50'. The space group is P21/m, with 2 base-pair complexes in the unit cell. The structure was refined with 3-dimensional data taken with Cu-radiation. The positional coordinates and anisotropic temp. factors of the heavy atoms were obtained by least-sqs. analyses. The H atoms, except those of 2 Me groups, were located from a 3-dimensional difference Fourier synthesis. The 1-methylthymine and 9-methyladenine mols. form a planar base pair lying in a mirror plane and are connected to one another by 2 nearly linear H bonds, from the NH2 group of 9-methyladenine to O(9) of 1-methylthymine (2.846 A.) and N(3) of 1-methylthymine to N(7) of 9-methyladenine (2.924 A.). This structure differs from the adenine-thymine pairing proposed by Watson and Crick [Nature 171, 737 (1953)], where N3 of thymine is H-bonded to N1 of adenine. The distance between the Me group at N1 of 1-methylthymine and the one at N9 of 9-methyladenine is 8.645 A., whereas this distance is 11.1 A. in the pairing proposed by W. and C. (CA 48, 5113d).
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  48. 48
    Zhang, S. L.; Michaelian, K. H.; Loppnow, G. R. Vibrational Spectra and Experimental Assignments of Thymine and Nine of Its Isotopomers. J. Phys. Chem. A 1998, 102, 461– 470,  DOI: 10.1021/jp972385m
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    48
    Vibrational Spectra and Experimental Assignments of Thymine and Nine of Its Isotopomers
    Zhang, Shuliang L.; Michaelian, Kirk H.; Loppnow, Glen R.
    Journal of Physical Chemistry A (1998), 102 (2), 461-470CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    FT-IR and FT-Raman spectra of polycryst. natural abundance thymine, nine of its isotopic derivs., and 2-thiothymine (5-methyl-2-thiouracil) are reported from 50 to 3500 cm-1. The isotopic derivs. are thymine-6-13C, thymine-α-13C, thymine-15N2, thymine-α,α,α,6-d4, and their resp. N-deuterated compds. The vibrational spectra are assigned using the frequency shifts upon isotopic substitution and are compared to previous assignments, both exptl. and ab initio based. Extensive mixing of the vibrations in the region below 1750 cm-1 complicates the vibrational assignments in this region. However, many of the exocyclic stretching and bending vibrations are assigned with confidence, and many of the couplings can be ascertained with these thymine derivs. The spectra of the isotopic derivs. described here resolve many of the controversial assignments in the literature and correct some previously misassigned vibrational bands. This represents the most complete exptl. vibrational study of thymine to date and provides a useful exptl. basis for future theor. calcns.
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  49. 49
    Peng, C. S.; Jones, K. C.; Tokmakoff, A. Anharmonic Vibrational Modes of Nucleic Acid Bases Revealed by 2D IR Spectroscopy. J. Am. Chem. Soc. 2011, 133, 15650– 15660,  DOI: 10.1021/ja205636h
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    49
    Anharmonic Vibrational Modes of Nucleic Acid Bases Revealed by 2D IR Spectroscopy
    Peng, Chunte Sam; Jones, Kevin C.; Tokmakoff, Andrei
    Journal of the American Chemical Society (2011), 133 (39), 15650-15660CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Polarization-dependent two-dimensional IR (2D IR) spectra of the purine and pyrimidine base vibrations of five nucleotide monophosphates (NMPs) were acquired in D2O at neutral pH in the frequency range 1500-1700 cm-1. The distinctive cross-peaks between the ring deformations and carbonyl stretches of NMPs indicate that these vibrational modes are highly coupled, in contrast with the traditional peak assignment, which is based on a simple local mode picture such as C=O, C=N, and C=C double bond stretches. A model of multiple anharmonically coupled oscillators was employed to characterize the transition energies, vibrational anharmonicities and couplings, and transition dipole strengths and orientations. No simple or intuitive structural correlations are found to readily assign the spectral features, except in the case of guanine and cytosine, which contain a single local CO stretching mode. To help interpret the nature of these vibrational modes, we performed d. functional theory (DFT) calcns. and found that multiple ring vibrations are coupled and delocalized over the purine and pyrimidine rings. Generally, there is close correspondence between the exptl. and computational results, provided that the DFT calcns. include explicit waters solvating hydrogen-bonding sites. These results provide direct exptl. evidence of the delocalized nature of the nucleotide base vibrations via a nonperturbative fashion and will serve as building blocks for constructing a structure-based model of DNA and RNA vibrational spectroscopy.
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  50. 50
    Leonard, G. A.; McAuleyhecht, K.; Brown, T.; Hunter, W. N. Do C-H...O Hydrogen-Bonds Contribute To The Stability Of Nucleic-Acid Base-Pairs. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1995, 51, 136– 139,  DOI: 10.1107/S0907444994004713
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    50
    Do C-H...O hydrogen bonds contribute to the stability of nucleic acid base pairs?
    Leonard G A; McAuley-Hecht K; Brown T; Hunter W N
    Acta crystallographica. Section D, Biological crystallography (1995), 51 (Pt 2), 136-9 ISSN:0907-4449.
    The possible formation of inter-base C-H.O hydrogen bonds in A.T, A.U and certain non-Watson-Crick base pairs is examined. A geometrical analysis in conjunction with implications for the thermodynamic stability of the base pairs suggests that C-H.O hydrogen bonds could form in nucleic acid base pairs. They may alleviate destabilizing interactions that would arise if an unsatisfied hydrogen-bond acceptor were present and mediate secondary hydrogen-bonding effects in these base pairs.
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  51. 51
    Ghosh, A.; Bansal, M. C–H···O hydrogen bonds in minor groove of A-tracts in DNA double helices. J. Mol. Biol. 1999, 294, 1149– 1158,  DOI: 10.1006/jmbi.1999.3323
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    51
    C-H..O Hydrogen Bonds in Minor Groove of A-tracts in DNA Double Helices
    Ghosh, Anirban; Bansal, Manju
    Journal of Molecular Biology (1999), 294 (5), 1149-1158CODEN: JMOBAK; ISSN:0022-2836. (Academic Press)
    Anal. of available B-DNA type oligomeric crystal structures as well as protein-bound DNA fragments (solved using data with resoln. <2.6 Å) indicates that in both data sets, a majority of the (3'-Ade) H2..O2(3'-Thy/Cyt) distances in AA.TT and GA.TC dinucleotide steps, are considerably shorter than their values in a uniform fiber model, and are smaller than their optimum sepn. distance. Since the electropos. C2-H2 group of adenine is in close proximity of the electroneg. keto oxygen atoms of both pyrimidine bases in the antiparallel strand of the double-helical DNA structures, it suggests the possibility of intra-base-pair as well as cross-strand C-H..O hydrogen bonds in the minor groove. The C2-H2..O2 hydrogen bonds within the A.T base-pairs could be a natural consequence of Watson-Crick pairing. However, the close cross-strand interactions between the bases at the 3'-ends of the AA.TT and GA.TC steps arise due to the local sequence-dependent geometry of these steps. While the base-pair propeller twist in these steps is comparable to the fiber model, some of the other local parameters such as base-pair opening angle and inter-base-pair slide show coordinated changes, leading to these shorter C2-H2..O2 distances. Hence, in addn. to the well-known minor groove hydration, it appears that favorable C2-H2..O2 cross-strand interactions may play a role in imparting a characteristic geometry to AA.TT and GA.TC steps, as well as An.Tn and GAn.TnC tracts, which leads to a narrow minor groove in these regions. (c) 1999 Academic Press.
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  52. 52
    Srinivasadesikan, V.; Sahu, P. K.; Lee, S.-L. Spectroscopic probe on N–H···N, N–H···O and controversial C–H···O contact in A–T base pair: A DFT study. Spectrochim. Acta, Part A 2014, 120, 542– 547,  DOI: 10.1016/j.saa.2013.11.110
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    52
    Spectroscopic probe on N-H···N, N-H···O and controversial C-H···O contact in A-T base pair: A DFT study
    Srinivasadesikan, Venkatesan; Sahu, Prabhat K.; Lee, Shyi-Long
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2014), 120 (), 542-547CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)
    DNA base pair A-T was studied by IR and NMR spectroscopy using DFT methods. The results were analyzed in terms of IR vibrational frequencies and 1H NMR chem. shifts. Different types of interactions N-H···N, N-H···O and C-H···O types were studied in DNA base pairs. Although, previous reports argued about the 3rd C-H···O type interaction in A-T base pair, such typical interaction was analyzed thoroughly by IR and NMR spectroscopy using DFT methods. The CH···O interaction in the A-T base pair is a weak interaction compared to normal hydrogen bond interactions.
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  53. 53
    Šponer, J.; Leszczynski, J.; Hobza, P. Structures and Energies of Hydrogen-Bonded DNA Base Pairs. A Nonempirical Study with Inclusion of Electron Correlation. J. Phys. Chem. A 1996, 100, 1965– 1974,  DOI: 10.1021/jp952760f
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    53
    Structures and Energies of Hydrogen-Bonded DNA Base Pairs. A Nonempirical Study with Inclusion of Electron Correlation
    Sponer, Jiri; Leszczynski, Jerzy; Hobza, Pavel
    Journal of Physical Chemistry (1996), 100 (5), 1965-74CODEN: JPCHAX; ISSN:0022-3654. (American Chemical Society)
    Hydrogen bonding of DNA bases was investigated by reliable nonempirical ab initio calcns. Gradient optimization was carried out on 30 DNA base pairs using the Hartree-Fock (HF) approxn. and the 6-31G** basis set of AOs. The optimizations were performed within Cs symmetry. However, the harmonic vibrational anal. indicates that 13 of the studied base pairs are intrinsically nonplanar. Interaction energies of base pairs were then evaluated at the planar optimized geometries with inclusion of the electron correlation energy using the second-order Moeller-Plesset (MP2) method. The stabilization energies of the studied base pairs range from -24 to -9 kcal/mol, and the calcd. gas phase interaction enthalpies agree well (within 2 kcal/mol) with the available exptl. values. The binding energies and mol. structures of the base pairs are not detd. solely by the hydrogen bonds, but they are also strongly influenced by the polarity of the monomers and by a wide variety of secondary long-range electrostatic interactions that also involve the hydrogen atoms bonded to ring carbon atoms. The stabilization of the base pairs is dominated by the Hartree-Fock interaction energy. This result confirms that the stability of the base pairs originates in the electrostatic interactions. For weakly bonded base pairs, the correlation interaction energy amts. to as much as 30-40% of the stabilization. For some other base pairs, however, repulsive correlation interaction energy was found. The latter fact is explained as a result of a redn. of the electrostatic attraction upon inclusion of the electron correlation. The empirical London dispersion energy does not reproduce the correlation interaction energy. For the sake of comparison, results of a first gradient optimization for a DNA base pair at a correlated level (CC base pair, MP2/6-31G** level) are reported. In addn., the ability of the economical d. functional theory (DFT) method to reproduce the ab initio data was investigated. The DFT method with present functionals is not suitable to consistently study the whole range of the DNA base interactions. However, it gives good ests. of interaction energies at the ref. HF/6-31G** geometries.
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  54. 54
    Shishkin, O. V.; Sponer, J.; Hobza, P. Intramolecular flexibility of DNA bases in adenine-thymine and guanine-cytosine Watson-Crick base pairs. J. Mol. Struct. 1999, 477, 15– 21,  DOI: 10.1016/S0022-2860(98)00603-6
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    54
    Intramolecular flexibility of DNA bases in adenine-thymine and guanine-cytosine Watson-Crick base pairs
    Shishkin, Oleg V.; Sponer, Jiri; Hobza, Pavel
    Journal of Molecular Structure (1999), 477 (1-3), 15-21CODEN: JMOSB4; ISSN:0022-2860. (Elsevier Science B.V.)
    The conformational flexibility of pyrimidine rings in adenine (A)-thymine (T) and guanine (G)-cytosine (C) Watson-Crick base pairs was investigated at the ab initio Hartree-Fock (HF) level using 6-31G** basis set. Transition of these rings from the planar equil. conformation to a distorted sofa conformation with torsion angles of 20° results in a marginal energy increase of approx. 1.3 kcal/mol for the A-T pair and 3.5 kcal/mol for the G-C pair. In the GC pair, the simultaneous deformation of both pyrimidine rings was applied. Comparison of ring deformation energies calcd. at the HF, with correlated levels indicates significant overestimation (up to 30%) of ring rigidity by the HF approxn. Reasonable correlations were found between the out-of-plane ring vibrational frequencies and the ring deformation energies. Formation of Watson-Crick base pairs is manifested in prolongation of the N-H bonds within the bases which results in significant redn. of the N-H stretching frequencies. On the basis of the calcd. increase in the C-H stretching frequency of adenine, the existence of a third hydrogen bond of the C-H···O type in the A-T pair is ruled out.
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  55. 55
    Shui, X.; Sines, C. C.; McFail-Isom, L.; VanDerveer, D.; Williams, L. D. Structure of the Potassium Form of CGCGAATTCGCG: DNA Deformation by Electrostatic Collapse around Inorganic Cations. Biochemistry 1998, 37, 16877– 16887,  DOI: 10.1021/bi982063o
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    55
    Structure of the Potassium Form of CGCGAATTCGCG: DNA Deformation by Electrostatic Collapse around Inorganic Cations
    Shui, Xiuqi; Sines, Chad C.; McFail-Isom, Lori; VanDerveer, Don; Williams, Loren Dean
    Biochemistry (1998), 37 (48), 16877-16887CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
    The potassium form of d(CGCGAATTCGCG) solved by x-ray diffraction to 1.75 Å resoln. indicates that monovalent cations penetrate the primary and secondary layers of the "spine of hydration". Both the sodium [Shui, X., McFail-Isom, L., Hu, G. G., and Williams, L. D. (1998) Biochem. 37, 8341-8355] and the potassium forms of the dodecamer at high resoln. indicate that the original description of the spine, only two layers deep and with full occupancy by water mols., requires substantive revision. The spine is merely the bottom two layers of a four layer solvent structure. The four layers combine to form a repeating motif of fused hexagons. The top two solvent layers were not apparent from previous medium-resoln. diffraction data. We propose that the narrow minor groove and axial curvature of A-tract DNA arise from localization of cations within the minor groove. In general, the results described here support a model in which most or all forces that drive DNA away from canonical B-conformation are extrinsic and arise from interaction of DNA with its environment. Intrinsic forces, originating from direct base-base interactions such as stacking, hydrogen bonding, and steric repulsion among exocyclic groups appear to be insignificant. The time-averaged positions of the ubiquitous inorg. cations that surround DNA are influenced by DNA bases. The distribution of cations depends on sequence. Regions of high and low cation d. are generated spontaneously in the solvent region by heterogeneous sequence or even within the grooves of homopolymers. The regions of high and low cation d. deform DNA by electrostatic collapse. Thus, the effects of small inorg. cations on DNA structure are similar to the effects of proteins.
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    Woods, K. K.; Lan, T.; McLaughlin, L. W.; Williams, L. D. The role of minor groove functional groups in DNA hydration. Nucleic Acids Res. 2003, 31, 1536– 1540,  DOI: 10.1093/nar/gkg240
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    The role of minor groove functional groups in DNA hydration
    Woods, Kristen Kruger; Lan, Tao; McLaughlin, Larry W.; Williams, Loren Dean
    Nucleic Acids Research (2003), 31 (5), 1536-1540CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Here we describe the crystal structure of modified [d(CGCGAATTCGCG)]2 refined to 2.04 Å. The modification, which affects only the two thymines at the central ApT step, involves isosteric removal of the 2-keto oxygen atoms and substitution of the N1 nitrogen with carbon. The crystal structure reveals the ability of this modified thymine to effectively base pair with adenine in [d(CGCGAAtTCGCG)]2. The structure also suggests that the minor groove "spine of hydration" is destabilized but essentially intact.
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    Schneider, B.; Berman, H. M. Hydration of the DNA bases is local. Biophys. J. 1995, 69, 2661– 2669,  DOI: 10.1016/S0006-3495(95)80136-0
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    Hydration of the DNA bases is local
    Schneider, Bohdan; Berman, Helen M.
    Biophysical Journal (1995), 69 (6), 2661-9CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
    Ordered hydration sites were detd. for the nucleotide bases in B-type conformations using the crystal structure data on 14 B-DNA decamer structures. A method of d. representation was extended so that positions, occupancies, and distributions of the hydration sites were predicted around a B-DNA double helix by a method analogous to crystallog. refinement. The predicted hydration sites correctly reproduce the main features of hydration around the B-DNA dodecamer. In contrast, to the previous observations, the newly available crystal data show the same extent of hydration of guanine and adenine, and of cytosine and thymine.
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    Shakked, Z.; Guzikevich-Guerstein, G.; Frolow, F.; Rabinovich, D.; Joachimiak, A.; Sigler, P. B. Determinants of repressor/operator recognition from the structure of the trp operator binding site. Nature 1994, 368, 469– 473,  DOI: 10.1038/368469a0
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    Determinants of repressor/operator recognition from the structure of the trp operator binding site
    Shakked, Z.; Guzikevich-Guerstein, G.; Frolow, F.; Rabinovich, D.; Joachimiak, A.; Sigler, P. B.
    Nature (London, United Kingdom) (1994), 368 (6470), 469-73CODEN: NATUAS; ISSN:0028-0836.
    On the basis of the crystal structure of the trp repressor/operator complex, it has been proposed that the specificity of the interaction can be explained not only by direct hydrogen bonding and non-polar contacts between the protein and the bases of its target DNA, but also by indirect structural effects and water-mediated interactions. To understand the contribution of DNA structure and hydration in this context, the structure of the free DNA must be compared with its structure when complexed with the protein. Here the authors present the high-resoln. crystal structure of the trp operator region that is most important in the recognition process. By comparing the free and bound states of the DNA regulatory sequence, the authors show that the structure and hydration of the DNA target are important elements in its recognition by the repressor protein.
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    Drew, H. R.; Wing, R. M.; Takano, T.; Broka, C.; Tanaka, S.; Itakura, K.; Dickerson, R. E. Structure of a B-DNA dodecamer: conformation and dynamics. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 2179,  DOI: 10.1073/pnas.78.4.2179
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    Structure of a B-DNA dodecamer. I. Conformation and dynamics
    Drew, Horace R.; Wing, Richard M.; Takano, Tsunehiro; Broka, Christopher; Tanaka, Shoji; Itakura, Keiichi; Dickerson, Richard E.
    Proceedings of the National Academy of Sciences of the United States of America (1981), 78 (4), 2179-83CODEN: PNASA6; ISSN:0027-8424.
    The crystal structure of the synthetic DNA dodecamer d(CpGpCpGpApApTpTpCpGpCpG) was refined to a residual error of R = 17.8% at 1.9-Å resoln. (2-σ data). The mol. forms slightly >1 complete turn of right-handed double-stranded B helix. The 2 ends of the helix overlap and interlock minor grooves with neighboring mols. up and down a 21 screw axis, producing a 19° bend in helix axis over the 11-base-pair steps of the dodecamer. In the center of the mol., where perturbation is least, the helix has a mean rotation of 36.9° per step, or 9.8 base pairs per turn. The mean propeller twist (total dihedral angle between base planes) between A·T base pairs in the center of the mol. is 17.3°, and that between C·G pairs on the 2 ends avs. 11.5°. Individual deoxyribose ring conformations, measured by the C5'-C4'-C3'-O3' torsion angle δ, exhibit an approx. Gaussian distribution centered around the C1'-exo position with δav. = 123° and a range of 79-157°. Purine sugars cluster at high δ values, and pyrimidine sugars cluster at lower δ. A tendency toward 2-fold symmetry in sugar conformation about the center of the mol. is detectable in spite of the destruction of ideal 2-fold symmetry by the mol. bending. More strikingly, sugar conformations of paired bases appear to follow a principle of anticorrelation, with δ values lying approx. the same distance to either side of the center value, δ = 123°. This same anticorrelation is also obsd. in other DNA and DNA·RNA structures.
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    Valls, N.; Wright, G.; Steiner, R. A.; Murshudov, G. N.; Subirana, J. A. DNA variability in five crystal structures of d (CGCAATTGCG). Spectrochim. Acta, Part A 2004, 60, 680– 685,  DOI: 10.1107/S0907444904002896
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    Edwards, K. J.; Brown, D. G.; Spink, N.; Skelly, J. V.; Neidle, S. Molecular structure of the B-DNA dodecamer d(CGCAAATTTGCG)2 An examination of propeller twist and minor-groove water structure at 2·2Åresolution. J. Mol. Biol. 1992, 226, 1161– 1173,  DOI: 10.1016/0022-2836(92)91059-X
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    61
    Molecular structure of the B-DNA dodecamer d(CGCAAATTTGCG)2. An examination of propeller twist and minor-groove water structure at 2.2Å resolution
    Edwards, Karen J.; Brown, David G.; Spink, Neil; Skelly, Jane V.; Neidle, Stephen
    Journal of Molecular Biology (1992), 226 (4), 1161-73CODEN: JMOBAK; ISSN:0022-2836.
    The crystal structure of the dodecanucleotide duplex d(CGCAAATTTGCG)2 has been solved to 2.2Å resoln. and refined to an R-factor of 18.1% with the inclusion of 71 water mols. The structure shows propeller twists of up to -20° for the A·T base-pairs, although there is probably only one (weak) three-center hydrogen bond in the six base-pair AT narrow minor-groove region. An extensive ribbon of hydration has been located in this groove that has features distinctive from the classic spine of hydration. Solvation around phosphate groups is described, with several instances of water mols. bridging between phosphates.
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    Larsen, T. A.; Kopka, M. L.; Dickerson, R. E. Crystal structure analysis of the B-DNA dodecamer CGTGAATTCACG. Biochemistry 1991, 30, 4443– 9,  DOI: 10.1021/bi00232a010
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    Crystal structure analysis of the B-DNA dodecamer CGTGAATTCACG
    Larsen, Teresa A.; Kopka, Mary L.; Dickerson, Richard E.
    Biochemistry (1991), 30 (18), 4443-9CODEN: BICHAW; ISSN:0006-2960.
    The crystal structure of the DNA dodecamer C-G-T-G-A-A-T-T-C-A-C-G has been detd. at a resoln. of 2.5 Å, with a final R factor of 15.8% for 1475 nonzero reflections measured at 0 °. The structure is isomorphous with that of the Drew dodecamer, with that space group P212121 and cell dimensions of a = 24.94 Å, b = 40.78 Å, and c = 66.13 Å. The asym. unit contains all 12 base pairs of the B-DNA double helix and 36 water mols. The structure of C-G-T-G-A-A-T-T-C-A-C-G is very similar to that of Drew dodecamer C-G-C-G-A-A-T-T-C-G-C-G, with no major alterations in helix parameters. A hierarchy of credibility of the local helix parameters at intermediate resoln. is proposed. In order of descending accuracy, these are (a) backbone pathway and minor-groove width, (b) base-pair long-axis parameters, such as twist and tilt, (c) base-pair short-axis parameters such as propeller, buckle, cup, and rise, and (d) sugar-ring conformation and main-chain torsion angles. Water peaks in the refined structure appear to represent a selection of peaks that were obsd. in the Drew dodecamer. The minor-grrove spine of hydration at 2.5 Å is fragmentary, but as N. Narendra et al. (1991) have obsd., lowering the temp. leads to a more complete representation of the spine.
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    Vlieghe, D.; Turkenburg, J. P.; Van Meervelt, L. B-DNA at atomic resolution reveals extended hydration patterns. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1999, 55, 1495– 502,  DOI: 10.1107/S0907444999007933
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    B-DNA at atomic resolution reveals extended hydration patterns
    Vlieghe, Dominique; Turkenburg, Johan P.; Van Meervelt, Luc
    Acta Crystallographica, Section D: Biological Crystallography (1999), D55 (9), 1495-1502CODEN: ABCRE6; ISSN:0907-4449. (Munksgaard International Publishers Ltd.)
    Despite the importance of hydration around DNA in the understanding of its conformation and interactions with other mols. in many biol. processes, only limited at. resoln. information is available. Crystal-engineering techniques, which were originally developed to mimic DNA base triplets in a crystal lattice, also eliminate the rotational disorder of oligonucleotides around their helical axis and thereby enhance the resoln. of the structure anal. The low-temp. crystal structure of the synthetic DNA decamer d(GGCCAATTGG) has been detd. at at. resoln. (1.15 A) using 17700 reflections and the highly organized hydration patterns in both grooves have been characterized. The narrow d(AATT) minor groove is occupied by an "extended hydration spine" alternately bridging base pairs and phosphate O1P atoms of opposite strands, while a distinctive pattern of parallel water ribbons is obsd. in the major groove. This anal. provides structural insight into the correlation found between narrow minor-groove width and occurrence of the BI conformation and can be used to design new minor-groove binders. By their location between adjacent helixes, two fully hydrated magnesium ions further stabilize the crystal packing. The structure also provides details of the hydration and conformation of G·GC triple helixes.
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    Liepinsh, E.; Otting, G.; Wüthrich, K. NMR observation of individual molecules of hydration water bound to DNA duplexes: direct evidence for a spine of hydration water present in aqueous solution. Nucleic Acids Res. 1992, 20, 6549– 6553,  DOI: 10.1093/nar/20.24.6549
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    64
    NMR observation of individual molecules of hydration water bound to DNA duplexes: direct evidence for a spine of hydration water present in aqueous solution
    Liepinsh, Edvards; Otting, Gottfried; Wuethrich, Kurt
    Nucleic Acids Research (1992), 20 (24), 6549-53CODEN: NARHAD; ISSN:0305-1048.
    The residence times of individual hydration water mols. in the major and minor grooves of DNA were measured by NMR spectroscopy in aq. solns. of d(CGCGAATTCGCG)2 and d(AAAAATTTTT)2. The exptl. observations were nuclear Overhauser effects (NOE) between water protons and the protons of the DNA. The pos. sign of NOEs with the thymine Me groups shows that the residence times of the hydration water mols. near these protons in the major groove of the DNA must be shorter than about 500 ps, which coincides with the behavior of surface hydration water in peptides and proteins. Neg. NOEs were obsd. with the hydrogen atoms in position 2 of adenine in both duplexes studied. This indicates that a spine of hydration in the minor groove, as obsd. by x-ray diffraction in DNA crystals, is present also in soln., with residence times significantly longer than 1 ns. Such residence times are reminiscent of interior hydration water mols. in globular proteins, which are an integral part of the mol. architecture both in soln. and in crystals.
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    Halle, B.; Denisov, V. P. Water and monovalent ions in the minor groove of B-DNA oligonucleotides as seen by NMR. Biopolymers 1998, 48, 210– 233,  DOI: 10.1002/(SICI)1097-0282(1998)48:4<210::AID-BIP3>3.0.CO;2-Y
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    Water and monovalent ions in the minor groove of B-DNA oligonucleotides as seen by NMR
    Halle B; Denisov V P
    Biopolymers (1998), 48 (4), 210-33 ISSN:0006-3525.
    During the past 8 years, two complementary nmr techniques-magnetic relaxation dispersion and nuclear Overhauser effect spectroscopy-have been applied extensively to the study of water and monovalent ions in the minor groove of B-DNA oligonucleotides in solution. In this review, the possibilities and limitations of the two methods are outlined, with emphasis on the interpretational steps whereby molecular-level information is extracted from the primary data. The results on sequence-dependent hydration and ion-DNA interactions obtained so far by these methods is summarized and critically assessed. The nmr results are also compared with structural data from x-ray crystallography.
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    Fingerhut, B. P.; Elsaesser, T. Noncovalent Interactions of Hydrated DNA and RNA Mapped by 2D-IR Spectroscopy. In Springer Series in Optical Sciences, Cho, M., Ed.; Springer Singapore: Singapore, 2019; Vol. 226, pp 171– 195.
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    Guchhait, B.; Liu, Y.; Siebert, T.; Elsaesser, T. Ultrafast vibrational dynamics of the DNA backbone at different hydration levels mapped by two-dimensional infrared spectroscopy. Struct. Dyn. 2015, 3, 043202  DOI: 10.1063/1.4936567
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    Siebert, T.; Guchhait, B.; Liu, Y.; Costard, R.; Elsaesser, T. Anharmonic Backbone Vibrations in Ultrafast Processes at the DNA–Water Interface. J. Phys. Chem. B 2015, 119, 9670– 9677,  DOI: 10.1021/acs.jpcb.5b04499
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    Anharmonic backbone vibrations in ultrafast processes at the DNA-water interface
    Siebert, Torsten; Guchhait, Biswajit; Liu, Yingliang; Costard, Rene; Elsaesser, Thomas
    Journal of Physical Chemistry B (2015), 119 (30), 9670-9677CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    The vibrational modes of the deoxyribose-phosphodiester backbone moiety of DNA and their interactions with the interfacial aq. environment were addressed with 2-dimensional (2D) IR spectroscopy on a femtosecond-to-picosecond time scale. Beyond the current understanding in the harmonic approxn., the anharmonic character and delocalization of the backbone modes in the frequency range of 900-1300 cm-1 were detd. with both diagonal anharmonicities and intermode couplings on the order of 10 cm-1. Mediated by the intermode couplings, energy transfer between the backbone modes took place on a picosecond time scale, parallel to vibrational relaxation and energy dissipation into the environment. Probing structural dynamics noninvasively via the time evolution of the 2D lineshapes, limited structural fluctuations were obsd. on a 300-fs time scale of low-frequency motions of the helix, counterions, and water shell. Structural disorder of the DNA-water interface and DNA-water H-bonds were, however, preserved for times beyond 10 ps. The different interactions of limited strength ensure ultrafast vibrational relaxation and dissipation of excess energy in the backbone structure, processes that are important for the structural integrity of hydrated DNA.
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    Yang, M.; Szyc, Ł.; Elsaesser, T. Decelerated Water Dynamics and Vibrational Couplings of Hydrated DNA Mapped by Two-Dimensional Infrared Spectroscopy. J. Phys. Chem. B 2011, 115, 13093– 13100,  DOI: 10.1021/jp208166w
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    69
    Decelerated Water Dynamics and Vibrational Couplings of Hydrated DNA Mapped by Two-Dimensional Infrared Spectroscopy
    Yang, Ming; Szyc, Lukasz; Elsaesser, Thomas
    Journal of Physical Chemistry B (2011), 115 (44), 13093-13100CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Double-stranded DNA oligomers contg. 23 alternating adenine-thymine base pairs are studied at different hydration levels by femtosecond 2-dimensional (2D) IR spectroscopy. Coupled NH stretching modes of the A-T pairs and OH stretching excitations of the H2O shell are discerned in the 2-dimensional spectra. Limited changes of NH stretching frequencies and line shapes with increasing hydration suggest spectral dynamics governed by DNA rather than H2O fluctuations. But OH stretching excitations of the H2O shell around fully hydrated DNA undergo spectral diffusion on a ∼ 500 fs time scale. The center line slopes of the 2-dimensional spectra of hydrated DNA demonstrate a slower decay of the frequency-time correlation function (TCF) than that in neat H2O, as is evident from a comparison with 2-dimensional spectra of neat H2O and theor. TCFs. The authors attribute this behavior to reduced structural fluctuations of the H2O shell and a reduced rate of resonant OH stretching energy transfer.
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    Feig, M.; Pettitt, B. M. Modeling high-resolution hydration patterns in correlation with DNA sequence and conformation11Edited by B. Honig. J. Mol. Biol. 1999, 286, 1075– 1095,  DOI: 10.1006/jmbi.1998.2486
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    Modeling High-resolution Hydration Patterns in Correlation with DNA Sequence and Conformation
    Feig, Michael; Pettitt, B. Montgomery
    Journal of Molecular Biology (1999), 286 (4), 1075-1095CODEN: JMOBAK; ISSN:0022-2836. (Academic Press)
    Hydration around the DNA fragment d(C5T5)·(A5G5) is presented from two mol. dynamics simulations of 10 and 12 ns total simulation time. The DNA has been simulated as a flexible mol. with both the CHARMM and AMBER force fields in explicit solvent including counterions and 0.8 M addnl. NaCl salt. From the previous anal. of the DNA structure B-DNA conformations were found with the AMBER force-field and A-DNA conformations with CHARMM parameters. High-resoln. hydration patterns are compared between the two conformations and between C·G and T·A base-pairs from the homopolymeric parts of the simulated sequence. Crystallog. results from a statistical anal. of hydration sites around DNA crystal structures compare very well with the simulation results. Differences between the crystal sites and our data are explained by variations in conformation, sequence, and limitations in the resoln. of water sites by crystal diffraction. Hydration layers are defined from radial distribution functions and compared with exptl. results. Excellent agreement is found when the measured exptl. quantities are compared with the equiv. distribution of water mols. in the first hydration shell. The no. of water mols. bound to DNA was found smaller around T·A base-pairs and around A-DNA as compared to B-DNA. This is partially offset by a larger no. of water mols. in hydrophobic contact with DNA around T·A base-pairs and around A-DNA. The nos. of water mols. in minor and major grooves have been correlated with helical roll, twist, and inclination angles. The data more fully explain the obsd. B A transition at low humidity. (c) 1999 Academic Press.
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    Young, M. A.; Jayaram, B.; Beveridge, D. L. Intrusion of Counterions into the Spine of Hydration in the Minor Groove of B-DNA: Fractional Occupancy of Electronegative Pockets. J. Am. Chem. Soc. 1997, 119, 59– 69,  DOI: 10.1021/ja960459m
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    71
    Intrusion of Counterions into the Spine of Hydration in the Minor Groove of B-DNA: Fractional Occupancy of Electronegative Pockets
    Young, Matthew A.; Jayaram, B.; Beveridge, D. L.
    Journal of the American Chemical Society (1997), 119 (1), 59-69CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    A sequence of ordered solvent peaks in the electron d. map of the minor groove region of ApT-rich tracts of the double helix is a characteristic of B-form DNA well established from crystallog. This feature, termed the "spine of hydration", has been discussed as a stabilizing feature of B-DNA, the structure of which is known to be sensitive to environmental effects. Nanosecond-range mol. dynamics simulations on the DNA duplex of sequence d(CGCGAATTCGCG) have been carried out, including explicit consideration of ∼4000 water mols. and 22 Na+ counterions, and based on the new AMBER 4.1 force field with the particle mesh Ewald summation used in the treatment of long-range interactions. The calcns. support a dynamical model of B-DNA closer to the B form than any previously reported. Anal. of the dynamical structure of the solvent revealed that, in over half of the trajectory, a Na+ ion is found in the minor groove localized at the ApT step. This position, termed herein the "ApT pocket", was noted previously (Lavery, R.; Pullman, B. J. Biomol. Struct. Dyn. 1985, 5, 1021) to be of uniquely low neg. electrostatic potential relative to other positions of the groove, a result supported by the location of a Na+ ion in the crystal structure of the dApU miniduplex [Seeman, N.; et al. J. Mol. Biol. 1976, 104, 109] and by addnl. calcns. described herein based on continuum electrostatics. The Na+ ion in the ApT pocket interacts favorably with the thymine O2 atom on opposite strands of the duplex and is well articulated with the water mols. which constitute the remainder of the minor groove spine. This result indicates that counterions may intrude on the minor groove spine of hydration on B-form DNA and subsequently influence the environmental structure and thermodn. in a sequence-dependent manner. The obsd. narrowing of the minor groove in the AATT region of the d(CGCGAATTCGCG) structure may be due to direct binding effects and also to indirect modulation of the electrostatic repulsions that occur when a counterion resides in the minor groove "AT pocket". The idea of localized complexation of otherwise mobile counterions in electroneg. pockets in the grooves of DNA helixes introduces a heretofore mostly unappreciated source of sequence-dependent effects on local conformational, helicoidal, and morphol. structure and may have important implications in understanding the functional energetics and specificity of the interactions of DNA and RNA with regulatory proteins, pharmaceutical agents, and other ligands.
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    Stelling, A. L.; Xu, Y.; Zhou, H.; Choi, S. H.; Clay, M. C.; Merriman, D. K.; Al-Hashimi, H. M. Robust IR-based detection of stable and fractionally populated G-C+ and A-T Hoogsteen base pairs in duplex DNA. FEBS Lett. 2017, 591, 1770– 1784,  DOI: 10.1002/1873-3468.12681
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    Robust IR-based detection of stable and fractionally populated G-C+ and A-T Hoogsteen base pairs in duplex DNA
    Stelling, Allison L.; Xu, Yu; Zhou, Huiqing; Choi, Seung H.; Clay, Mary C.; Merriman, Dawn K.; Al-Hashimi, Hashim M.
    FEBS Letters (2017), 591 (12), 1770-1784CODEN: FEBLAL; ISSN:0014-5793. (Wiley-Blackwell)
    Noncanonical G-C+ and A-T Hoogsteen base pairs can form in duplex DNA and play roles in recognition, damage repair, and replication. Identifying Hoogsteen base pairs in DNA duplexes remains challenging due to difficulties in resolving syn vs. antipurine bases with x-ray crystallog.; and size limitations and line broadening can make them difficult to characterize by NMR spectroscopy. Here, it was shown that IR spectroscopy can identify G-C+ and A-T Hoogsteen base pairs in duplex DNA across a range of different structural contexts. The utility of IR-based detection of Hoogsteen base pairs is demonstrated by characterizing the first example of adjacent A-T and G-C+ Hoogsteen base pairs in a DNA duplex where severe broadening complicates detection with NMR.
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    Damha, M. J.; Ogilvie, K. K. Oligoribonucleotide Synthesis. In Protocols for Oligonucleotides and Analogs; Springer, 1993; Vol. 20, pp 81– 114.
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    Xu, Y.; McSally, J.; Andricioaei, I.; Al-Hashimi, H. M. Modulation of Hoogsteen dynamics on DNA recognition. Nat. Commun. 2018, 9, 1473  DOI: 10.1038/s41467-018-03516-1
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    Modulation of Hoogsteen dynamics on DNA recognition
    Xu Yu; Al-Hashimi Hashim M; Xu Yu; Al-Hashimi Hashim M; McSally James; Andricioaei Ioan
    Nature communications (2018), 9 (1), 1473 ISSN:.
    In naked duplex DNA, G-C and A-T Watson-Crick base pairs exist in dynamic equilibrium with their Hoogsteen counterparts. Here, we used nuclear magnetic resonance (NMR) relaxation dispersion and molecular dynamics (MD) simulations to examine how Watson-Crick/Hoogsteen dynamics are modulated upon recognition of duplex DNA by the bisintercalator echinomycin and monointercalator actinomycin D. In both cases, DNA recognition results in the quenching of Hoogsteen dynamics at base pairs involved in intermolecular base-specific hydrogen bonds. In the case of echinomycin, the Hoogsteen population increased 10-fold for base pairs flanking the chromophore most likely due to intermolecular stacking interactions, whereas actinomycin D minimally affected Hoogsteen dynamics at other sites. Modulation of Hoogsteen dynamics at binding interfaces may be a general phenomenon with important implications for DNA-ligand and DNA-protein recognition.
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    Gilbert, D. E.; Feigon, J. Proton NMR study of the [d(ACGTATACGT)]2-2echinomycin complex: conformational changes between echinomycin binding sites. Nucleic Acids Res. 1992, 20, 2411– 2420,  DOI: 10.1093/nar/20.10.2411
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    Proton NMR study of the [d(ACGTATACGT)]2-2echinomycin complex: conformational changes between echinomycin binding sites
    Gilbert, Dara E.; Feigon, Juli
    Nucleic Acids Research (1992), 20 (10), 2411-20CODEN: NARHAD; ISSN:0305-1048.
    The interactions of echinomycin and the DNA decamer [d(ACGTATACGT)]2 were studied by proton NMR. Echinomycin binds cooperatively as a bisintercalator at the CpG steps. The terminal A-T base pairs are Hoogsteen base paired, but none of the four central A-T base pairs are Hoogsteen base paired. However, binding of the drug induces unwinding of the DNA which is propagated to the central ApT step. All four central A-T base pairs are destabilized relative to those in the free DNA. Furthermore, based on these and other results, the authors conclude that the formation of stable Hoogsteen base pairs may not be the relevant structural change in vivo. The structural changes propagated between adjacent ACGT binding sites are the unwinding of the duplex and destabilization of the base pairing between binding sites.
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    Gilbert, D. E.; Feigon, J. The DNA sequence at echinomycin binding sites determines the structural changes induced by drug binding: NMR studies of echinomycin binding to [d (ACGTACGT)] 2 and [d (TCGATCGA)] 2. Biochemistry 1991, 30, 2483– 2494,  DOI: 10.1021/bi00223a027
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    The DNA sequence at echinomycin binding sites determines the structural changes induced by drug binding: NMR studies of echinomycin binding to [d(ACGTACGT)]2 and [d(TCGATCGA)]2
    Gilbert, Dara E.; Feigon, Juli
    Biochemistry (1991), 30 (9), 2483-94CODEN: BICHAW; ISSN:0006-2960.
    The complexes formed between the cyclic octadepsipeptide antibiotic echinomycin and the two DNA octamers [d(ACGTACGT)]2 and [d(TCGATCGA)]2 were investigated by using one- and two-dimensional proton NMR spectroscopy techniques. The results obtained for the two complexes are compared with each other, with the crystal structures of related DNA-echinomycin complexes, and with enzymic and chem. footprinting results. In the satd. complexes, two echinomycin mols. bind to each octamer by bisintercalation of the quinoxaline moieties on either side of each CpG step. Binding of echinomycin to the octamer [d(ACGTACGT)]2 is cooperative so that only the two-drug complex is obsd. at lower drug-DNA ratios, but binding to [d(TCGATCGA)]2 is not cooperative. At low temps., both the internal and terminal A·T base pairs adjacent to the binding site in the [d(ACGTACGT)]2-2 echinomycin complex are Hoogsteen base paired as obsd. in related crystal structures. However, as the temp. is raised, the internal A·T Hoogsteen base pairs are destabilized and are obsd. to be exchanging between the Hoogsteen base-paired and an open (or Watson-Crick base-paired) state. In contrast, in the [d(TCGATCGA)]2-2 echinomycin complex, no A·T Hoogsteen base pairs are obsd., the internal A·T base pairs appear to be stabilized by drug binding, and the structure of the complex does not change significantly from 0 to 45°. Thus, the structure and stability of the DNA in echinomycin-DNA complexes depends on the sequence at and adjacent to the binding site. While no single structural change in the DNA can explain all of the footprinting results, unwinding of the DNA helix in the drug-DNA complexes appears to be an important factor while Hoogsteen base pair formation does not.
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    Gao, X.; Patel, D. J. Antitumour drug-DNA interactions: NMR studies of echinomycin and chromomycin complexes. Q. Rev. Biophys. 1989, 22, 93– 138,  DOI: 10.1017/S0033583500003814
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    Antitumor drug-DNA interactions: NMR studies of echinomycin and chromomycin complexes
    Gao, Xiaolian; Patel, Dinshaw J.
    Quarterly Reviews of Biophysics (1989), 22 (2), 93-138CODEN: QURBAW; ISSN:0033-5835.
    A review with 54 refs.
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    Gilbert, D. E.; van der Marel, G. A.; van Boom, J. H.; Feigon, J. Unstable Hoogsteen base pairs adjacent to echinomycin binding sites within a DNA duplex. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 3006– 3010,  DOI: 10.1073/pnas.86.9.3006
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    Unstable Hoogsteen base pairs adjacent to echinomycin binding sites within a DNA duplex
    Gilbert, Dara E.; Van der Marel, Gijs A.; Van Boom, Jacques H.; Feigon, Juli
    Proceedings of the National Academy of Sciences of the United States of America (1989), 86 (9), 3006-10CODEN: PNASA6; ISSN:0027-8424.
    The bis-intercalation complex present between the DNA octamer [d(ACGTACGT)]2 and the cyclic octadepsipeptide antibiotic echinomycin (I) has been studied by one- and two-dimensional proton NMR, and the results obtained have been compared with the crystal structures of related DNA-echinomycin complexes. Two echinomycins bind cooperatively to each DNA duplex at the CpG steps, with the two quinoxaline rings of each echinomycin bis-intercalating between the C·G and A·T base pairs. At low temps., the A·T base pairs on either side of the intercalation site adopt the Hoogsteen conformation, as obsd. in the crystal structures. As the temp. is raised, the Hoogsteen base pairs in the interior of the duplex are destabilized and are obsd. to be exchanging between the Hoogsteen base pair and either an open or a Watson-Crick base-paired state. The terminal A·T base pairs, which are not as constrained by the helix as the internal base pairs, remain stably Hoogsteen base-paired up to at least 45°. The implications of these results for the biol. role of Hoogsteen base pairs in echinomycin-DNA complexes in vivo are discussed.
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    Gao, X.; Patel, D. J. NMR studies of echinomycin bisintercalation complexes with d (A1-C2-G3-T4) and d (T1-C2-G3-A4) duplexes in aqueous solution: sequence-dependent formation of Hoogsteen A1-T4 and Watson-Crick T1-A4 base pairs flanking the bisintercalation site. Biochemistry 1988, 27, 1744– 1751,  DOI: 10.1021/bi00405a054
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    NMR studies of echinomycin bisintercalation complexes with d(A1-C2-G3-T4) and d(T1-C2-G3-A4) duplexes in aqueous solution: sequence-dependent formation of Hoogsteen A1·T4 and Watson-Crick T1·A4 base pairs flanking the bisintercalation site
    Gao, Xiaolian; Patel, Dinshaw J.
    Biochemistry (1988), 27 (5), 1744-51CODEN: BICHAW; ISSN:0006-2960.
    Two-dimensional 1H NMR studies of echinomycin complexes with the self-complementary d(A1-C2-G3-T4) and d(T1-C2-G3-A4) duplexes in aq. soln. are reported. The exchangeable and nonexchangeable antibiotic and nucleic acid 1Hs in the 1 echinomycin per tetranucleotide duplex complexes were assigned from analyses of scalar coupling and distance connectivities in 2-dimensional data sets recorded in H2O and D2O soln. An anal. of the intermol. NOE patterns for both complexes combined with large upfield imino 1H and large downfield P complexation chem. shift changes demonstrates that the 2 quinoxaline chromophores of echinomycin bisintercalate into the minor groove surrounding the dC-dG step of each tetranucleotide duplex. Further, the quinoxaline rings selectively stack between A1 and C2 bases in the d(ACGT) complex and between T1 and C2 bases in the d(TCGA) complex. The intermol. NOE patterns and the base and sugar proton chem. shifts for residues C2 and G3 are virtually identical for the d(ACGT) and d(TCGA) complexes. These and other results reported here emphasize the role of sequence in discriminating between Watson-Crick and Hoogsteen pairs at base pairs flanking the echinomycin bisintercalation site in soln.
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  80. 80
    Xu, Y.; Manghrani, A.; Liu, B.; Shi, H.; Pham, U.; Liu, A.; Al-Hashimi, H. M. Hoogsteen base pairs increase the susceptibility of double-stranded DNA to cytotoxic damage. J. Biol. Chem. 2020, 295, 15933– 15947,  DOI: 10.1074/jbc.RA120.014530
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    Hoogsteen base pairs increase the susceptibility of double-stranded DNA to cytotoxic damage
    Xu, Yu; Manghrani, Akanksha; Liu, Bei; Shi, Honglue; Pham, Uyen; Liu, Amy; Al-Hashimi, Hashim M.
    Journal of Biological Chemistry (2020), 295 (47), 15933-15947CODEN: JBCHA3; ISSN:1083-351X. (American Society for Biochemistry and Molecular Biology)
    As the Watson-Crick faces of nucleobases are protected in dsDNA, it is commonly assumed that deleterious alkylation damage to the Watson-Crick faces of nucleobases predominantly occurs when DNA becomes single-stranded during replication and transcription. However, damage to the Watson-Crick faces of nucleobases has been reported in dsDNA in vitro through mechanisms that are not understood. In addn., the extent of protection from methylation damage conferred by dsDNA relative to ssDNA has not been quantified. Watson-Crick base pairs in dsDNA exist in dynamic equil. with Hoogsteen base pairs that expose the Watson-Crick faces of purine nucleobases to solvent. Whether this can influence the damage susceptibility of dsDNA remains unknown. Using dot-blot and primer extension assays, we measured the susceptibility of adenine-N1 to methylation by di-Me sulfate (DMS) when in an A-T Watson-Crick vs. Hoogsteen conformation. Relative to unpaired adenines in a bulge, Watson-Crick A-T base pairs in dsDNA only conferred ~ 130-fold protection against adenine-N1 methylation, and this protection was reduced to ~ 40-fold for A(syn)-T Hoogsteen base pairs embedded in a DNA-drug complex. Our results indicate that Watson-Crick faces of nucleobases are accessible to alkylating agents in canonical dsDNA and that Hoogsteen base pairs increase this accessibility. Given the higher abundance of dsDNA relative to ssDNA, these results suggest that dsDNA could be a substantial source of cytotoxic damage. The work establishes DMS probing as a method for characterizing A(syn)-T Hoogsteen base pairs in vitro and also lays the foundation for a sequencing approach to map A(syn)-T Hoogsteen and unpaired adenines genome-wide in vivo.
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  81. 81
    Leng, F.; Chaires, J. B.; Waring, M. J. Energetics of echinomycin binding to DNA. Nucleic Acids Res. 2003, 31, 6191– 6197,  DOI: 10.1093/nar/gkg826
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    Energetics of echinomycin binding to DNA
    Leng, Fenfei; Chaires, Jonathan B.; Waring, Michael J.
    Nucleic Acids Research (2003), 31 (21), 6191-6197CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Differential scanning calorimetry and UV thermal denaturation have been used to det. a complete thermodn. profile for the bis-intercalative interaction of the peptide antibiotic echinomycin with DNA. The new calorimetric data are consistent with all previously published binding data, and afford the most rigorous and direct detn. of the binding enthalpy possible. For the assocn. of echinomycin with DNA, the authors found ΔG° = -7.6 kcal mol-1, ΔH = +3.8 kcal mol-1 and ΔS = +38.9 cal mol-1 K-1 at 20°. The binding reaction is clearly entropically driven, a hallmark of a process that is predominantly stabilized by hydrophobic interactions, though a deeper anal. of the free energy contributions suggests that direct mol. recognition between echinomycin and DNA, mediated by hydrogen bonding and van der Waals contacts, also plays an important role in stabilizing the complex.
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    Frey, M. N.; Koetzle, T. F.; Lehmann, M. S.; Hamilton, W. C. Precision neutron diffraction structure determination of protein and nucleic acid components. XII. A study of hydrogen bonding in the purine-pyrimidine base pair 9-methyladenine · 1-methylthymine. J. Chem. Phys. 1973, 59, 915– 924,  DOI: 10.1063/1.1680114
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    Precision neutron diffraction structure determination of protein and nucleic acid components. XII. Hydrogen bonding in the purine-pyrimidine base pair 9-methyladenine . 1-methylthymine
    Frey, Michel N.; Koetzle, Thomas F.; Lehmann, Mogens S.; Hamilton, Walter C.
    Journal of Chemical Physics (1973), 59 (2), 915-24CODEN: JCPSA6; ISSN:0021-9606.
    A neutron diffraction study of the 1:1 complex between 9-methyladenine and 1-methylthymine, C6H7N5.C6H8N2O2, was carried out. The structure is monoclinic, space group P21/m, with 2 base pairs per unit cell; cell parameters a 8.304(2), b 6.552(2), c 12.837(3) Å, and β 106.83(5)°. The structure was refined by full-matrix least squares techniques starting from the x-ray results of Hoogsteen (1959 and 1963). All H atoms were located with a precision better than 0.01 Å, with the exception of Me group H. The thymine mols. appear to be slightly disordered by means of a 180° rotation about N3...C6, which has the effect of interchanging N1 and C5 while leaving the positions of all other atoms approx. unchanged. Between 10% and 13% of the thymine mols. in the structure are disordered in this way. Av. refined neutron scattering lengths for N and C are b‾N = 0.910(3) and b‾C = 0.657(3) × 10-12 cm; O and H scattering lengths were fixed at b‾H = -0.372 and bO = 0.575 × 10-12 cm. The purine and pyrimidine bases are joined with N3 of thymine H bonded to N7 of adenine. Because of the disorder present in the structure, 87-90% of the adenine.thymine pairs have the Hoogsteen configuration and the remainder have the reversed Hoogsteen configuration. These geometries differ from that of a Watson-Crick adenine.thymine pair in which N3 of thymine donates a proton to N1 of adenine. The H bonding scheme in the cryst. complex consists of one N-H...N and two N-H...O bonds and is quite normal; there is no evidence for proton transfer in any of the H bonds which are formed.
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    King, M. D.; Ouellette, W.; Korter, T. M. Noncovalent Interactions in Paired DNA Nucleobases Investigated by Terahertz Spectroscopy and Solid-State Density Functional Theory. J. Phys. Chem. A 2011, 115, 9467– 9478,  DOI: 10.1021/jp111878h
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    Noncovalent Interactions in Paired DNA Nucleobases Investigated by Terahertz Spectroscopy and Solid-State Density Functional Theory
    King, Matthew D.; Ouellette, Wayne; Korter, Timothy M.
    Journal of Physical Chemistry A (2011), 115 (34), 9467-9478CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    Cocrystd. adenine and thymine derivs., along with the pure monomeric crystals, were investigated by terahertz spectroscopy and solid-state d. functional theory (DFT). The methylated nucleobase derivs. crystallize in planar hydrogen-bonded adenine-thymine pairs similar to the manner found in DNA. The spectra obtained for 1-methylthymine, 9-methyladenine, and the 1:1 cocrystal in the range of 10-100 cm-1 clearly demonstrate that absorptions in this spectral range originate from the uniquely ordered assembly and the intermol. interactions found in each individual crystal system. The quality of spectral reprodn. for the DFT simulations of each system was clearly improved by the inclusion of an empirical correction term for London-type dispersion forces to the calcns. Notably, it was found that these weak dispersion forces in the adenine-thymine cocrystal were necessary to produce a properly converged crystal structure and meaningful simulation of the terahertz vibrational spectrum.
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    Jarzembska, K. N.; Goral, A. M.; Gajda, R.; Dominiak, P. M. Hoogsteen–Watson–Crick 9-Methyladenine:1-Methylthymine Complex: Charge Density Study in the Context of Crystal Engineering and Nucleic Acid Base Pairing. Cryst. Growth Des. 2013, 13, 239– 254,  DOI: 10.1021/cg301393e
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    Hoogsteen-Watson-Crick 9-Methyladenine:1-Methylthymine Complex: Charge Density Study in the Context of Crystal Engineering and Nucleic Acid Base Pairing
    Jarzembska, Katarzyna N.; Goral, Anna M.; Gajda, Roman; Dominiak, Paulina M.
    Crystal Growth & Design (2013), 13 (1), 239-254CODEN: CGDEFU; ISSN:1528-7483. (American Chemical Society)
    This study provides a detailed charge d. distribution anal. supported by comprehensive energetic investigations. The nature of the intermol. interactions existing in the 9-methyladenine:1-methylthymine cocrystal structure (9mAc:1mTc) with respect to those specific for the corresponding monocomponent crystals is explored. Charge d. topol. investigations lead to reliable hydrogen-bond interaction energies consistent with the results of the DFT approach with Grimme dispersion correction applied. The cocrystal structure cohesive energy corresponds with the av. stability of its components' crystals. This is in agreement with the exptl. observations. Thus, formation of the particularly strong 9-methyladenine:1-methylthymine motif (interaction energy around -70 kJ·mol-1, DFT(B3LYP)/pVTZ, BSSE and dispersive corrections applied) may constitute the driving force for cocrystal growth. All three systems form mol. layers governed by hydrogen-bond interactions whereas interacting mostly dispersively with each other. The interlayer contacts are found to be significant. Formation of particularly short H···H contacts is a distinctive feature of the cocrystal lattice. Also, creation of the cis-Hoogsteen-Watson-Crick (cHW) adenine-thymine base pair motif (Leontis and Westhof classification), instead of creating the most frequently appearing DNA Watson-Crick base pair (cWW), is remarkable. It occurs that this A:U/T orientation is slightly more stable than the analogous cWW one. Nevertheless, in RNA chains, being more flexible than DNA mols., the cHW A:U base pairing remains rather rarely encountered, which is probably the effect of the rigidity of nucleic acid chain backbones. In general, the purine-pyrimidine interaction strength is most sensitive to the directionality of the formed hydrogen bonds.
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    The calculation of small molecular interactions by the differences of separate total energies. Some procedures with reduced errors
    Boys, S. F.; Bernardi, F.
    Molecular Physics (1970), 19 (4), 553-566CODEN: MOPHAM; ISSN:0026-8976. (Taylor & Francis Ltd.)
    A new direct difference method for the computation of mol. interactions has been based on a bivariational transcorrelated treatment, together with special methods for the balancing of other errors. It appears that these new features can give a strong redn. in the error of the interaction energy, and they seem to be particularly suitable for computations in the important region near the min. energy. It has been generally accepted that this problem is dominated by unresolved difficulties and the relation of the new methods of these apparent difficulties is analyzed here.
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    Lee, C.; Park, K.-H.; Cho, M. Vibrational dynamics of DNA. I. Vibrational basis modes and couplings. J. Chem. Phys. 2006, 125, 114508  DOI: 10.1063/1.2213257
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    Vibrational dynamics of DNA. I. Vibrational basis modes and couplings
    Lee, Chewook; Park, Kwang-Hee; Cho, Minhaeng
    Journal of Chemical Physics (2006), 125 (11), 114508/1-114508/16CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Carrying out d. functional theory calcns. of 4 DNA bases, base derivs., Watson-Crick (WC) base pairs, and multiple-layer base pair stacks, the authors studied vibrational dynamics of delocalized modes with frequency ranging from 1400 to 1800 cm-1. These modes have been found to be highly sensitive to structure fluctuation and base pair conformation of DNA. By identifying eight fundamental basis modes, it is shown that the normal modes of base pairs and multilayer base pair stacks can be described by linear combinations of these vibrational basis modes. By using the Hessian matrix reconstruction method, vibrational coupling consts. between the basis modes are detd. for WC base pairs and multilayer systems and are found to be most strongly affected by the hydrogen bonding interaction between bases. It is also found that the propeller twist and buckle motions do not strongly affect vibrational couplings and basis mode frequencies. Numerically simulated IR spectra of guanine-cytosine and adenine-thymine bases pairs as well as of multilayer base pair stacks are presented and described in terms of coupled basis modes. It turns out that, due to the small interlayer base-base vibrational interactions, the IR absorption spectrum of multilayer base pair system does not strongly depend on the no. of base pairs.
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    Yarasi, S.; Billinghurst, B. E.; Loppnow, G. R. Vibrational properties of thymine, uracil and their isotopomers. J. Raman Spectrosc. 2007, 38, 1117– 1126,  DOI: 10.1002/jrs.1722
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    Vibrational properties of thymine, uracil and their isotopomers
    Yarasi, Soujanya; Billinghurst, Brant E.; Loppnow, Glen R.
    Journal of Raman Spectroscopy (2007), 38 (9), 1117-1126CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
    D. functional theory (DFT) calcns. using the B3LYP/6-311G(d,p) basis set of ten isotopomers of thymine and four isotopomers of uracil, including the natural abundance isotopomers, are reported. Comparison of the calcd. wavenumber shifts upon hydrogen, carbon and nitrogen isotopic substitution with those from exptl. Raman and IR measurements show good agreement in both the direction and the magnitude of the shift. These results are contrasted to previously reported calcns. and discussed in the context of assigning the normal modes of thymine and uracil.
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    Manalo, M. N.; Kong, X.; LiWang, A. JNH Values Show that N1···N3 Hydrogen Bonds Are Stronger in dsRNA A:U than dsDNA A:T Base Pairs. J. Am. Chem. Soc. 2005, 127, 17974– 17975,  DOI: 10.1021/ja055826l
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    1JNH Values Show that N1···N3 Hydrogen Bonds Are Stronger in dsRNA A:U than dsDNA A:T Base Pairs
    Manalo, Marlon N.; Kong, Xiangming; LiWang, Andy
    Journal of the American Chemical Society (2005), 127 (51), 17974-17975CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Here, we show that 1JNH values are on av. 0.4 Hz less neg. for double-stranded RNA A:U than for DNA A:T base pairs, which according to existing theory, suggests that RNA N1···N3 hydrogen bond distances are about 0.02 Å shorter than those of DNA. Also, there is a statistically relevant trend between 1JNH and 2hΔ13C2 values, which supports the original hypothesis that 2hΔ13C2 values are also sensitive to hydrogen bond distances. Finally, a context dependence is obsd. for these values, which suggests that hydrogen-bonding and base-stacking interactions are coupled.
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    Cuesta-Seijo, J. A.; Sheldrick, G. M. Structures of complexes between echinomycin and duplex DNA. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2005, 61, 442– 448,  DOI: 10.1107/S090744490500137X
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    Structures of complexes between echinomycin and duplex DNA
    Cuesta-Seijo, Jose A.; Sheldrick, George M.
    Acta Crystallographica, Section D: Biological Crystallography (2005), D61 (4), 442-448CODEN: ABCRE6; ISSN:0907-4449. (Blackwell Publishing Ltd.)
    The structure of the bis-intercalation complex of the depsipeptide antibiotic echinomycin with (CGTACG)2 has been redetd. at a higher resoln. (1.4 Å) and new high-resoln. structures (1.1-1.5 Å) are reported for the complexes of echinomycin with (GCGTACGC)2 (at both low and high ionic strengths) and (ACGTACGT)2. The structures show the expected Hoogsteen pairing for the base pairs flanking the intercalating chromophores on the outside and Watson-Crick pairing for both base pairs enclosed by the echinomycin. In the octamer complexes but not the hexamer complex, the echinomycin mol., which would possess a mol. twofold axis were it not for the thioacetal bridge, shows twofold disorder. In all the structures the stacking of the base pairs and chromophores is extended by intermol. stacking. The structures provide more precise details of the hydrogen bonding and other interactions between the bis-intercalating antibiotics and the duplex DNA than were previously available.
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    Kong, D.; Park, E. J.; Stephen, A. G.; Calvani, M.; Cardellina, J. H.; Monks, A.; Fisher, R. J.; Shoemaker, R. H.; Melillo, G. Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity. Cancer Res. 2005, 65, 9047– 55,  DOI: 10.1158/0008-5472.CAN-05-1235
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    Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity
    Kong, Dehe; Park, Eun Jung; Stephen, Andrew G.; Calvani, Maura; Cardellina, John H.; Monks, Anne; Fisher, Robert J.; Shoemaker, Robert H.; Melillo, Giovanni
    Cancer Research (2005), 65 (19), 9047-9055CODEN: CNREA8; ISSN:0008-5472. (American Association for Cancer Research)
    The identification of small mols. that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1α and HIF-1β proteins contg. the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1α and HIF-1β proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide contg. a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compds. previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-mol. library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compds. identified, echinomycin (NSC-13502), a small-mol. known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay expts. showed that NSC-13502 inhibited binding of HIF-1α and HIF-1β proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-κB (NF-κB) consensus sequences. Interestingly, chromatin immunopptn. expts. showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-κB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small mols. that inhibit HIF-1 DNA binding to endogenous promoters.
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    Schneider, S. H.; Kratochvil, H. T.; Zanni, M. T.; Boxer, S. G. Solvent-Independent Anharmonicity for Carbonyl Oscillators. J. Phys. Chem. B 2017, 121, 2331– 2338,  DOI: 10.1021/acs.jpcb.7b00537
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    Solvent-Independent Anharmonicity for Carbonyl Oscillators
    Schneider, Samuel H.; Kratochvil, Huong T.; Zanni, Martin T.; Boxer, Steven G.
    Journal of Physical Chemistry B (2017), 121 (10), 2331-2338CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    The phys. origins of vibrational frequency shifts were extensively studied to understand noncovalent intermol. interactions in the condensed phase. In the case of carbonyls, vibrational solvatochromism, MD simulations, and vibrational Stark spectroscopy suggest that the frequency shifts obsd. in simple solvents arise predominately from the environment's elec. field due to the vibrational Stark effect. This is contrary to many previously invoked descriptions of vibrational frequency shifts, such as bond polarization, whereby the bond's force const. and/or partial nuclear charges are altered due to the environment, often illustrated in terms of favored resonance structures. These hypotheses were tested using vibrational solvatochromism as measured using 2D IR to assess the solvent dependence of the bond anharmonicity. The carbonyl bond's anharmonicity is independent of solvent as tested using hexanes, DMSO, and D2O and is supported by simulated 2D spectra. In support of the linear vibrational Stark effect, these 2D IR measurements are consistent with the assertion that the Stark tuning rate is unperturbed by the elec. field generated by both H and non-H bonding environments and further extends the general applicability of carbonyl probes for studying intermol. interactions.
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    Jiang, Y.; Wang, L. Modeling the vibrational couplings of nucleobases. J. Chem. Phys. 2020, 152, 084114  DOI: 10.1063/1.5141858
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    Modeling the vibrational couplings of nucleobases
    Jiang, Yaoyukun; Wang, Lu
    Journal of Chemical Physics (2020), 152 (8), 084114CODEN: JCPSA6; ISSN:0021-9606. (American Institute of Physics)
    Vibrational spectroscopy, in particular IR spectroscopy, has been widely used to probe the three-dimensional structures and conformational dynamics of nucleic acids. As commonly used chromophores, the C:O and C:C stretch modes in the nucleobases exhibit distinct spectral features for different base pairing and stacking configurations. To elucidate the origin of their structural sensitivity, the authors develop transition charge coupling (TCC) models that allow one to efficiently calc. the interactions or couplings between the C:O and C:C chromophores based on the geometric arrangements of the nucleobases. To evaluate their performances, the authors apply the TCC models to DNA and RNA oligonucleotides with a variety of secondary and tertiary structures and demonstrate that the predicted couplings are in quant. agreement with the ref. values. The authors further elucidate how the interactions between the paired and stacked bases give rise to characteristic IR absorption peaks and show that the TCC models provide more reliable predictions of the coupling consts. as compared to the transition dipole coupling scheme. The TCC models, together with the authors' recently developed through-bond coupling consts. and vibrational frequency maps, provide an effective theor. strategy to model the vibrational Hamiltonian, and hence the vibrational spectra of nucleic acids in the base carbonyl stretch region directly from atomistic mol. simulations. (c) 2020 American Institute of Physics.
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    Fritzsch, R.; Greetham, G. M.; Clark, I. P.; Minnes, L.; Towrie, M.; Parker, A. W.; Hunt, N. T. Monitoring Base-Specific Dynamics during Melting of DNA–Ligand Complexes Using Temperature-Jump Time-Resolved Infrared Spectroscopy. J. Phys. Chem. B 2019, 123, 6188– 6199,  DOI: 10.1021/acs.jpcb.9b04354
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    95
    Monitoring base-specific dynamics during melting of DNA-Ligand complexes using temperature-jump time-resolved infrared spectroscopy
    Fritzsch, Robby; Greetham, Gregory M.; Clark, Ian P.; Minnes, Lucy; Towrie, Michael; Parker, Anthony W.; Hunt, Neil T.
    Journal of Physical Chemistry B (2019), 123 (29), 6188-6199CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Ultrafast time-resolved IR spectroscopy employing nanosecond temp.-jump initiation has been used to study the melting of double-stranded (ds) DNA oligomers in the presence and absence of minor groove-binding ligand Hoechst 33258. Ligand binding to ds(5'-GCAAATTTCC-3'), which binds Hoechst 33258 in the central A-tract region with nanomolar affinity, causes a dramatic increase in the timescales for strand melting from 30 to ∼250 μs. Ligand binding also suppresses premelting disruption of the dsDNA structure, which takes place on 100 ns timescales and includes end-fraying. In contrast, ligand binding to the ds(5'-GCATATATCC-3') sequence, which exhibits an order of magnitude lower affinity for Hoechst 33258 than the A-tract motif, leads to an increase by only a factor of 5 in melting timescales and reduced suppression of premelting sequence perturbation and end-fraying. These results demonstrate a dynamic impact of the minor groove ligand on the dsDNA structure that correlates with binding strength and thermodn. stabilization of the duplex. Moreover, the ability of the ligand to influence base pairs distant from the binding site has potential implications for allosteric communication mechanisms in dsDNA.
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  96. 96
    Ramakers, L. A. I.; Hithell, G.; May, J. J.; Greetham, G. M.; Donaldson, P. M.; Towrie, M.; Parker, A. W.; Burley, G. A.; Hunt, N. T. 2D-IR Spectroscopy Shows that Optimized DNA Minor Groove Binding of Hoechst33258 Follows an Induced Fit Model. J. Phys. Chem. B 2017, 121, 1295– 1303,  DOI: 10.1021/acs.jpcb.7b00345
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    96
    2D-IR Spectroscopy Shows that Optimized DNA Minor Groove Binding of Hoechst33258 Follows an Induced Fit Model
    Ramakers, Lennart A. I.; Hithell, Gordon; May, John J.; Greetham, Gregory M.; Donaldson, Paul M.; Towrie, Michael; Parker, Anthony W.; Burley, Glenn A.; Hunt, Neil T.
    Journal of Physical Chemistry B (2017), 121 (6), 1295-1303CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    The induced-fit binding model describes a conformational change occurring when a small mol. binds to its biomacromol. target. The result is enhanced noncovalent interactions between ligand and biomol. Induced fit is well-established for small mol.-protein interactions, but its relevance to small mol.-DNA binding is less clear. Here, the authors investigated the mol. determinants of Hoechst 33258 binding to its preferred A-tract sequence relative to a sub-optimal alternating A-T sequence. The results from 2-dimensional FTIR spectroscopy, which is sensitive to H-bonding and mol. structure changes, showed that Hoechst 33258 binding resulted in a loss of minor groove spine of hydration in both sequences, but an addnl. perturbation of the base propeller twists occurred in the A-tract binding region. This induced-fit maximizes favorable ligand-DNA enthalpic contributions in the optimal binding case and demonstrates that controlling the mol. details that induce subtle changes in DNA structure may hold the key to designing next-generation DNA-binding mols.
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  97. 97
    Hithell, G.; González-Jiménez, M.; Greetham, G. M.; Donaldson, P. M.; Towrie, M.; Parker, A. W.; Burley, G. A.; Wynne, K.; Hunt, N. T. Ultrafast 2D-IR and optical Kerr effect spectroscopy reveal the impact of duplex melting on the structural dynamics of DNA. Phys. Chem. Chem. Phys. 2017, 19, 10333– 10342,  DOI: 10.1039/C7CP00054E
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    97
    Ultrafast 2D-IR and optical Kerr effect spectroscopy reveal the impact of duplex melting on the structural dynamics of DNA
    Hithell, Gordon; Gonzalez-Jimenez, Mario; Greetham, Gregory M.; Donaldson, Paul M.; Towrie, Michael; Parker, Anthony W.; Burley, Glenn A.; Wynne, Klaas; Hunt, Neil T.
    Physical Chemistry Chemical Physics (2017), 19 (16), 10333-10342CODEN: PPCPFQ; ISSN:1463-9076. (Royal Society of Chemistry)
    Changes in the structural and solvation dynamics of a 15mer AT DNA duplex upon melting of the double-helix are obsd. by a combination of ultrafast two-dimensional IR (2D-IR) and optical Kerr-effect (OKE) spectroscopies. 2D-IR spectroscopy of the vibrational modes of the DNA bases reveal signature off-diagonal peaks arising from coupling and energy transfer across Watson-Crick paired bases that are unique to double-stranded DNA (ds-DNA). Spectral diffusion of specific base vibrational modes report on the structural dynamics of the duplex and the minor groove, which is predicted to contain a spine of hydration. Changes in these dynamics upon melting are assigned to increases in the degree of mobile solvent access to the bases in single-stranded DNA (ss-DNA) relative to the duplex. OKE spectra exhibit peaks that are assigned to specific long-range phonon modes of ds- and ss-DNA. Temp.-related changes in these features correlate well with those obtained from the 2D-IR spectra although the melting temp. of the ds-DNA phonon band is slightly higher than that for the Watson-Crick modes, suggesting that a degree of long-range duplex structure survives the loss of Watson-Crick hydrogen bonding. These results demonstrate that the melting of ds-DNA disrupts helix-specific structural dynamics encompassing length scales ranging from mode delocalization in the Watson-Crick base pairs to long-range phonon modes that extend over multiple base pairs and which may play a role in mol. recognition of DNA.
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  98. 98
    Delaney, J. C.; Essigmann, J. M. Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 14051,  DOI: 10.1073/pnas.0403489101
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    98
    Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli
    Delaney, James C.; Essigmann, John M.
    Proceedings of the National Academy of Sciences of the United States of America (2004), 101 (39), 14051-14056CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    AlkB repairs 1-alkyladenine and 3-methylcytosine lesions in DNA by directly reversing the base damage. Although repair studies with randomly alkylated substrates have been performed, the miscoding nature of these and related individually alkylated bases and the suppression of mutagenesis by AlkB within cells have not yet been explored. Here, we address the miscoding potential of 1-methyldeoxyadenosine (m1A), 3-methyldeoxycytidine (m3C), 3-ethyldeoxycytidine (e3C), 1-methyldeoxyguanosine (m1G), and 3-methyldeoxythymidine (m3T) by synthesizing single-stranded vectors contg. each alkylated base, followed by vector passage through Escherichia coli. In SOS-, AlkB-deficient cells, m1A was only 1% mutagenic; however, m3C and e3C were 30% mutagenic, rising to 70% in SOS+ cells. In contrast, the mutagenicity of m1G and m3T in AlkB- cells dropped slightly when SOS polymerases were expressed (m1G from 80% to 66% and m3T from 60% to 53%). Mutagenicity was abrogated for m1A, m3C, and e3C in wild-type (AlkB+) cells, whereas m3T mutagenicity was only partially reduced. Remarkably, m1G mutagenicity was also eliminated in AlkB+ cells, establishing it as a natural AlkB substrate. All lesions were blocks to replication in AlkB-deficient cells. The m1A, m3C, and e3C blockades were completely removed in wild-type cells; the m1G blockade was partially removed and that for m3T was unaffected by the presence of AlkB. All lesions demonstrated enhanced bypass when SOS polymerases were induced. This work provides direct evidence that AlkB suppresses both genotoxicity and mutagenesis by physiol. realistic low doses of 1-alkylpurine and 3-alkylpyrimidine DNA damage in vivo.
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  99. 99
    Yang, H.; Zhan, Y.; Fenn, D.; Chi, L. M.; Lam, S. L. Effect of 1-methyladenine on double-helical DNA structures. FEBS Lett. 2008, 582, 1629– 1633,  DOI: 10.1016/j.febslet.2008.04.013
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    99
    Effect of 1-methyladenine on double-helical DNA structures
    Yang, Hao; Zhan, Yingqian; Fenn, Dickson; Chi, Lai Man; Lam, Sik Lok
    FEBS Letters (2008), 582 (11), 1629-1633CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)
    Methylation at the N1 site of adenine leads to the formation of cytotoxic 1-methyladenine (m1A). Since the N1 site of adenine is involved in the hydrogen bonding of T·A and A·T Watson-Crick base pairs, it is expected that the pairing interactions will be disrupted upon 1-methylation. In this study, high-resoln. NMR investigations were performed to det. the effect of m1A on double-helical DNA structures. Interestingly, instead of disrupting hydrogen bonding, we found that 1-methylation altered the T·A Watson-Crick base pair to T(anti)·m1A(syn) Hoogsteen base pair, providing insights into the obsd. differences in AlkB-repair efficiency between dsDNA and ssDNA.
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  100. 100
    Yang, H.; Lam, S. L. Effect of 1-methyladenine on thermodynamic stabilities of double-helical DNA structures. FEBS Lett. 2009, 583, 1548– 1553,  DOI: 10.1016/j.febslet.2009.04.017
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    100
    Effect of 1-methyladenine on thermodynamic stabilities of double-helical DNA structures
    Yang, Hao; Lam, Sik Lok
    FEBS Letters (2009), 583 (9), 1548-1553CODEN: FEBLAL; ISSN:0014-5793. (Elsevier B.V.)
    1-Methyladenine (m1A) alters T·A Watson-Crick to T·m1A Hoogsteen base pair. Owing to its conversion to N6-methyladenine (m6A) at higher temps., thermodn. studies of m1A-contg. DNAs using conventional melting methods are subject to the influence of m6A species. In this study, we applied NMR spectroscopy to det. the base pairing modes and effect of m1A on thermodn. stability of double-helical DNA. The obsd. base pairing modes account for the destabilizing trend which follows the order T·m1A ∼ G·m1A < A·m1A < C·m1A, providing insights into the m1A flipping process and enhancing our understandings of the mutagenicity of m1A.
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  101. 101
    Sathyamoorthy, B.; Shi, H.; Zhou, H.; Xue, Y.; Rangadurai, A.; Merriman, D. K.; Al-Hashimi, H. M. Insights into Watson–Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A. Nucleic Acids Res. 2017, 45, 5586– 5601,  DOI: 10.1093/nar/gkx186
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    101
    Insights into Watson-Crick/Hoogsteen breathing dynamics and damage repair from the solution structure and dynamic ensemble of DNA duplexes containing m1A
    Sathyamoorthy, Bharathwaj; Shi, Honglue; Zhou, Huiqing; Xue, Yi; Rangadurai, Atul; Merriman, Dawn K.; Al-Hashimi, Hashim M.
    Nucleic Acids Research (2017), 45 (9), 5586-5601CODEN: NARHAD; ISSN:1362-4962. (Oxford University Press)
    In the canonical DNA double helix, Watson-Crick (WC) base pairs (bps) exist in dynamic equil. with sparsely populated (∼0.02-0.4%) and shortlived (lifetimes ∼0.2-2.5 ms) Hoogsteen (HG) bps. To gain insights into transient HG bps, we used soln.-state NMR spectroscopy, including measurements of residual dipolar couplings and mol. dynamics simulations, to examine how a single HG bp trapped using the N1-methylated adenine (m1A) lesion affects the structural and dynamic properties of two duplexes. The soln. structure and dynamic ensembles of the duplexes reveals that in both cases, m1A forms a m1A·T HG bp, which is accompanied by local and global structural and dynamic perturbations in the double helix. These include a bias toward the BI backbone conformation; sugar repuckering, major-groove directed kinking (∼9°); and local melting of neighboring WC bps. These results provide at. insights into WC/HG breathing dynamics in unmodified DNA duplexes as well as identify structural and dynamic signatures that could play roles in m1A recognition and repair.
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  102. 102
    Zhou, H.; Kimsey, I. J.; Nikolova, E. N.; Sathyamoorthy, B.; Grazioli, G.; McSally, J.; Bai, T.; Wunderlich, C. H.; Kreutz, C.; Andricioaei, I.; Al-Hashimi, H. M. m(1)A and m(1)G disrupt A-RNA structure through the intrinsic instability of Hoogsteen base pairs. Nat. Struct. Mol. Biol. 2016, 23, 803– 810,  DOI: 10.1038/nsmb.3270
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    102
    m1A and m1G disrupt A-RNA structure through the intrinsic instability of Hoogsteen base pairs
    Zhou, Huiqing; Kimsey, Isaac J.; Nikolova, Evgenia N.; Sathyamoorthy, Bharathwaj; Grazioli, Gianmarc; McSally, James; Bai, Tianyu; Wunderlich, Christoph H.; Kreutz, Christoph; Andricioaei, Ioan; Al-Hashimi, Hashim M.
    Nature Structural & Molecular Biology (2016), 23 (9), 803-810CODEN: NSMBCU; ISSN:1545-9993. (Nature Publishing Group)
    The B-DNA double helix can dynamically accommodate G-C and A-T base pairs in either Watson-Crick or Hoogsteen configurations. Here, we show that G-C+ (in which + indicates protonation) and A-U Hoogsteen base pairs are strongly disfavored in A-RNA. As a result,N1-methyladenosine and N1-methylguanosine, which occur in DNA as a form of alkylation damage and in RNA as post-transcriptional modifications, have dramatically different consequences. Whereas they create G-C+ and A-T Hoogsteen base pairs in duplex DNA, thereby maintaining the structural integrity of the double helix, they block base-pairing and induce local duplex melting in RNA. These observations provide a mechanism for disrupting RNA structure through post-transcriptional modifications. The different propensities to form Hoogsteen base pairs in B-DNA and A-RNA may help cells meet the opposing requirements of maintaining genome stability, on the one hand, and of dynamically modulating the structure of the epitranscriptome, on the other.
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  103. 103
    Zhou, H.; Hintze, B. J.; Kimsey, I. J.; Sathyamoorthy, B.; Yang, S.; Richardson, J. S.; Al-Hashimi, H. M. New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey. Nucleic Acids Res. 2015, 43, 3420– 3433,  DOI: 10.1093/nar/gkv241
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    103
    New insights into Hoogsteen base pairs in DNA duplexes from a structure-based survey
    Zhou, Huiqing; Hintze, Bradley J.; Kimsey, Isaac J.; Sathyamoorthy, Bharathwaj; Yang, Shan; Richardson, Jane S.; Al-Hashimi, Hashim M.
    Nucleic Acids Research (2015), 43 (7), 3420-3433CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    Hoogsteen (HG) base pairs (bps) provide an alternative pairing geometry to Watson-Crick (WC) bps and can play unique functional roles in duplex DNA. Here, we use structural features unique to HG bps (syn purine base, HG hydrogen bonds and constricted C1'-C1' distance across the bp) to search for HG bps in X-ray structures of DNA duplexes in the Protein Data Bank. The survey identifies 106 A•T and 34 G•C HG bps in DNA duplexes, many of which are undocumented in the literature. It also uncovers HG-like bps with syn purines lacking HG hydrogen bonds or constricted C1'-C1' distances that are analogous to conformations that have been proposed to populate the WC-to-HG transition pathway. The survey reveals HG preferences similar to those obsd. for transient HG bps in soln. by NMR, including stronger preferences for A•T vs. G•C bps, TA vs. GG steps, and also suggests enrichment at terminal ends with a preference for 5'-purine. HG bps induce small local perturbations in neighboring bps and, surprisingly, a small but significant degree of DNA bending (∼14°) directed toward the major groove. The survey provides insights into the preferences and structural consequences of HG bps in duplex DNA.
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  104. 104
    Alvey, H. S.; Gottardo, F. L.; Nikolova, E. N.; Al-Hashimi, H. M. Widespread Transient Hoogsteen Base-Pairs in Canonical Duplex DNA with Variable Energetics. Nat. Commun. 2014, 5, 4786  DOI: 10.1038/ncomms5786
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    104
    Widespread transient Hoogsteen base pairs in canonical duplex DNA with variable energetics
    Alvey, Heidi S.; Gottardo, Federico L.; Nikolova, Evgenia N.; Al-Hashimi, Hashim M.
    Nature Communications (2014), 5 (), 4786CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    Hoogsteen (HG) base pairing involves a 180° rotation of the purine base relative to Watson-Crick (WC) base pairing within DNA duplexes, creating alternative DNA conformations that can play roles in recognition, damage induction and replication. Here, using NMR R1ρ relaxation dispersion, we show that transient HG base pairs occur across more diverse sequence and positional contexts than previously anticipated. We observe sequence-specific variations in HG base pair energetic stabilities that are comparable with variations in WC base pair stability, with HG base pairs being more abundant for energetically less favorable WC base pairs. Our results suggest that the variations in HG stabilities and rates of formation are dominated by variations in WC base pair stability, suggesting a late transition state for the WC-to-HG conformational switch. The occurrence of sequence and position-dependent HG base pairs provide a new potential mechanism for achieving sequence-dependent DNA transactions.
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  105. 105
    Nikolova, E. N.; Gottardo, F. L.; Al-Hashimi, H. M. Probing Transient Hoogsteen Hydrogen Bonds in Canonical Duplex DNA Using NMR Relaxation Dispersion and Single-Atom Substitution. J. Am. Chem. Soc. 2012, 134, 3667– 3670,  DOI: 10.1021/ja2117816
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    105
    Probing Transient Hoogsteen Hydrogen Bonds in Canonical Duplex DNA Using NMR Relaxation Dispersion and Single-Atom Substitution
    Nikolova, Evgenia N.; Gottardo, Federico L.; Al-Hashimi, Hashim M.
    Journal of the American Chemical Society (2012), 134 (8), 3667-3670CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Nucleic acids transiently morph into alternative conformations that can be difficult to characterize at the at. level by conventional methods because they exist for too little time and in too little abundance. The authors recently reported evidence for transient Hoogsteen (HG) base pairs in canonical B-DNA based on NMR carbon relaxation dispersion. While the carbon chem. shifts measured for the transient state were consistent with a syn orientation for the purine base, as expected for A(syn)·T(anti) and G(syn)·C+(anti) HG base pairing, HG type hydrogen bonding could only be inferred indirectly. Here, the authors develop two independent approaches for directly probing transient changes in N-H···N hydrogen bonds and apply them to the characterization of transient Hoogsteen type hydrogen bonds in canonical duplex DNA. The first approach takes advantage of the strong dependence of the imino nitrogen chem. shift on hydrogen bonding and involves measurement of R1ρ relaxation dispersion for the hydrogen-bond donor imino nitrogens in G and T residues. In the second approach, the authors assess the consequence of substituting the hydrogen-bond acceptor nitrogen (N7) with a carbon (C7H7) on both carbon and nitrogen relaxation dispersion data. Together, these data allow the authors to obtain direct evidence for transient Hoogsteen base pairs that are stabilized by N-H···N type hydrogen bonds in canonical duplex DNA. The methods introduced here greatly expand the utility of NMR in the structural characterization of transient states in nucleic acids.
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  106. 106
    Nikolova, E. N.; Kim, E.; Wise, A. A.; O’Brien, P. J.; Andricioaei, I.; Al-Hashimi, H. M. Transient Hoogsteen base pairs in canonical duplex DNA. Nature 2011, 470, 498– 502,  DOI: 10.1038/nature09775
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    106
    Transient Hoogsteen base pairs in canonical duplex DNA
    Nikolova, Evgenia N.; Kim, Eunae; Wise, Abigail A.; O'Brien, Patrick J.; Andricioaei, Ioan; Al-Hashimi, Hashim M.
    Nature (London, United Kingdom) (2011), 470 (7335), 498-502CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Sequence-directed variations in the canonical DNA double helix structure that retain Watson-Crick base-pairing have important roles in DNA recognition, topol. and nucleosome positioning. By using NMR relaxation dispersion spectroscopy in concert with steered mol. dynamics simulations, we have obsd. transient sequence-specific excursions away from Watson-Crick base-pairing at CA and TA steps inside canonical duplex DNA towards low-populated and short-lived A·T and G·C Hoogsteen base pairs. The observation of Hoogsteen base pairs in DNA duplexes specifically bound to transcription factors and in damaged DNA sites implies that the DNA double helix intrinsically codes for excited state Hoogsteen base pairs as a means of expanding its structural complexity beyond that which can be achieved based on Watson-Crick base-pairing. The methods presented here provide a new route for characterizing transient low-populated nucleic acid structures, which we predict will be abundant in the genome and constitute a second transient layer of the genetic code.
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  107. 107
    Kyogoku, Y.; Higuchi, S.; Tsuboi, M. Intra-red absorption spectra of the single crystals of 1-methyl-thymine, 9-methyladenine and their 1:1 complex. Spectrochim. Acta, Part A 1967, 23, 969– 983,  DOI: 10.1016/0584-8539(67)80022-9
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    107
    Infrared absorption spectra of the single crystals of 1-methylthymine, 6-methyladenine, and their 1:1 complex
    Kyogoku, Yoshimasa; Higuchi, Shigesada; Tsuboi, Masamichi
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (1967), 23 (4), 969-83CODEN: SAMCAS; ISSN:1386-1425.
    The IR absorption spectra have been observed of thin sections of the single crystals of 1-methylthymine, 9-methyladenine, and their hydrobonded 1:1 complex (AT dimer) by using the polarized radiation in the spectral region of 4000-400 cm.-1 The absorption bands due to the in-plane and out-of-plane vibrations are distinguished in the spectra of the sections perpendicular to the mol. plane. The directions of the transition moments were detd. of some of the absorption bands in the spectra of the sections parallel to the mol. plane. Assignments of the absorption bands due to the NH and NH2 deformation were made on the basis of the observed N-deuteration effects. A marked difference was observed between the spectra of the AT dimer and an equimolar mech. mixt. of 1-methylthymine and 9-methyladenine. The frequencies assignable to the out-of-plane vibrations of the NH and NH2 groups were sensitive to the manner of their H bonding. 24 references.
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    Etter, M. C.; Reutzel, S. M.; Choo, C. G. Self-organization of adenine and thymine in the solid state. J. Am. Chem. Soc. 1993, 115, 4411– 4412,  DOI: 10.1021/ja00063a089
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    108
    Self-organization of adenine and thymine in the solid state
    Etter, Margaret C.; Reutzel, Susan M.; Choo, Carolyn G.
    Journal of the American Chemical Society (1993), 115 (10), 4411-12CODEN: JACSAT; ISSN:0002-7863.
    Phase transformations from 2 unique reagent phases to a single cocrystal phase most often take place when the product cocrystal has stronger H bonds than either of the reagent crystals. The principle of spontaneous organization appears to hold for the nucleotide base pair, 9-methyladenine (A) and 1-methylthymine (T), where complexation is obsd. by simply grinding the 2 cryst. solids together at room temp. X-ray powder diffraction and FTIR spectroscopy, which are used to probe the selectivity of H-bond directed cocrystn., show that mols. of A and T aggregate into a Hoogsteen base pair in the grinding product. Remarkably, only this naturally occurring base is obsd., even when ternary mixt. of A, T, and 1 of the noncomplementary nucleotide bases, 9-ethylguanine (G) or 1-methylcytosine (C), are ground together.
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  109. 109
    Kyogoku, Y.; Higuchi, S.; Tsuboi, M. Infrared absorption spectra of the single crystals of 1-methyl-thymine, 9-methyladenine and their 1:1 complex. Spectrochim. Acta, Part A 1967, 23, 969– 983,  DOI: 10.1016/0584-8539(67)80022-9
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    109
    Infrared absorption spectra of the single crystals of 1-methylthymine, 6-methyladenine, and their 1:1 complex
    Kyogoku, Yoshimasa; Higuchi, Shigesada; Tsuboi, Masamichi
    Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (1967), 23 (4), 969-83CODEN: SAMCAS; ISSN:1386-1425.
    The IR absorption spectra have been observed of thin sections of the single crystals of 1-methylthymine, 9-methyladenine, and their hydrobonded 1:1 complex (AT dimer) by using the polarized radiation in the spectral region of 4000-400 cm.-1 The absorption bands due to the in-plane and out-of-plane vibrations are distinguished in the spectra of the sections perpendicular to the mol. plane. The directions of the transition moments were detd. of some of the absorption bands in the spectra of the sections parallel to the mol. plane. Assignments of the absorption bands due to the NH and NH2 deformation were made on the basis of the observed N-deuteration effects. A marked difference was observed between the spectra of the AT dimer and an equimolar mech. mixt. of 1-methylthymine and 9-methyladenine. The frequencies assignable to the out-of-plane vibrations of the NH and NH2 groups were sensitive to the manner of their H bonding. 24 references.
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    The electrophilic properties of 34 solvents were characterized by the Acceptor Number (AN) which is derived from 31P NMR measurements of Et3PO dissolved in the respective solvents. Relationships are found between the acceptor nos. and the Z-values, ET-values, and Y-values, as well as the free energies of solvation of anions, and the redox potentials of the hexacyanoferrate(III)-hexacyanoferrate(II) system in different solvents. The new parameter provides-together with the donor no.-a useful guide in choosing the most appropriate solvent for a given reaction.
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    The dependence of thymine and thymidine Raman spectra on solvent
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    Canadian Journal of Chemistry (2004), 82 (6), 1092-1101CODEN: CJCHAG; ISSN:0008-4042. (National Research Council of Canada)
    Recent work has focused on developing Raman spectroscopy as a noninvasive probe of DNA interactions with solvents, intercalants, proteins, and other ligands. Here, we report the Raman spectra of thymine in eight solvents and thymidine in nine solvents obtained with visible excitation. Raman spectra under acidic, neutral, and basic conditions were also obtained of both thymine and thymidine. Changes in both the frequencies and intensities of several of the vibrational bands in the 800-1800 cm-1 region are obsd. No evidence of deprotonation in the different solvents is obsd. for either thymine or thymidine. Correlations of the obsd. frequency shifts of specific vibrational modes with characteristic properties of the solvent for both thymine and thymidine show a significant correlation with acceptor and donor nos., measures of the hydrogen-bonding ability of the solvent, in both thymine and thymidine. These results are interpreted in terms of hydrogen-bonding interactions between the N-H protons of the thymine base and lone pairs of electrons on the solvent mols. and between the solvent hydrogens and lone pairs on C=O sites. The solvent-dependent intensity in vibrational bands of thymine between 1500 and 1800 cm-1 indicates a strong interaction between thymine and solvent at the C=O and N-H sites that leads to sepn. of the C=O stretches from the C=C stretch. The intensity variations with solvent were much smaller for thymidine than for thymine, perhaps as a result of replacing the N1 proton by the sugar. These results suggest that Raman spectroscopy is uniquely sensitive to specific interactions of thymine and thymidine with their environment.
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    Raman and Infrared Spectra of Thymine. A Matrix Isolation and DFT Study
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    Journal of Physical Chemistry A (2000), 104 (16), 3852-3863CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
    The Raman spectrum has been measured for thymine isolated in an Ar matrix using an FTRA instrument with IR excitation at 1.064 μm, thereby avoiding complications due to resonance Raman and fluorescence effects. This spectrum is used, together with the newly measured IR spectrum, to establish the assignment of the vibrational spectra of isolated thymine. The assignment is assisted by DFT calcns. made at the B3LYP/6-31G(d,p) level of theory, using GAUSSIAN 98W. The calcd. spectra, including the Raman spectrum, are in surprisingly good agreement with the exptl. spectra. The discrepancies that are obsd. for some parts of the spectrum result primarily from the failure of the harmonic approxn. made in the calcn. The effect of the neglect of anharmonicity has been investigated by detg. a set of effective force consts. that reproduce the exptl. frequencies and intensity patterns in the IR and Raman spectra and by examg. how the predicted spectra (intensities, frequencies, potential energy distributions (PEDs), IR intensity distributions (IDs), and Raman intensity distributions (RIDs)) change. The final results provide an unambiguous assignment of the vibrational spectra for thymine isolated in an Ar matrix and illustrate that the concepts of PEDs, IDs, and RIDs are useful for the interpretation of the vibrational spectra of mols. the size of the pyrimidine bases. Comparison of the Raman spectrum of thymine isolated in the Ar matrix with that of a polycryst. sample indicates that they are quite similar, in marked contrast to the differences in the corresponding IR spectra.
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    Carbon-Oxygen Hydrogen Bonding in Biological Structure and Function
    Horowitz, Scott; Trievel, Raymond C.
    Journal of Biological Chemistry (2012), 287 (50), 41576-41582CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    A review. Carbon-oxygen (CH···O) hydrogen bonding represents an unusual category of mol. interactions first documented in biol. structures over 4 decades ago. Although CH···O hydrogen bonding has remained generally underappreciated in the biochem. literature, studies over the last 15 years have begun to yield direct evidence of these interactions in biol. systems. In this minireview, we provide a historical context of biol. CH···O hydrogen bonding and summarize some major advancements from exptl. studies over the past several years that have elucidated the importance, prevalence, and functions of these interactions. In particular, we examine the impact of CH···O bonds on protein and nucleic acid structure, mol. recognition, and enzyme catalysis and conclude by exploring overarching themes and unresolved questions regarding unconventional interactions in biomol. structure.
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    Shi, H.; Clay, M. C.; Rangadurai, A.; Sathyamoorthy, B.; Case, D. A.; Al-Hashimi, H. M. Atomic structures of excited state A–T Hoogsteen base pairs in duplex DNA by combining NMR relaxation dispersion, mutagenesis, and chemical shift calculations. J. Biomol. NMR 2018, 70, 229– 244,  DOI: 10.1007/s10858-018-0177-2
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    Atomic structures of excited state A-T Hoogsteen base pairs in duplex DNA by combining NMR relaxation dispersion, mutagenesis, and chemical shift calculations
    Shi, Honglue; Clay, Mary C.; Rangadurai, Atul; Sathyamoorthy, Bharathwaj; Case, David A.; Al-Hashimi, Hashim M.
    Journal of Biomolecular NMR (2018), 70 (4), 229-244CODEN: JBNME9; ISSN:0925-2738. (Springer)
    NMR relaxation dispersion studies indicate that in canonical duplex DNA, Watson-Crick base pairs (bps) exist in dynamic equil. with short-lived low abundance excited state Hoogsteen bps. N1-methylated adenine (m1A) and guanine (m1G) are naturally occurring forms of damage that stabilize Hoogsteen bps in duplex DNA. NMR dynamic ensembles of DNA duplexes with m1A-T Hoogsteen bps reveal significant changes in sugar pucker and backbone angles in and around the Hoogsteen bp, as well as kinking of the duplex towards the major groove. Whether these structural changes also occur upon forming excited state Hoogsteen bps in unmodified duplexes remains to be established because prior relaxation dispersion probes provided limited information regarding the sugar-backbone conformation. Here, we demonstrate measurements of C3 and C4 spin relaxation in the rotating frame (R1ρ) in uniformly 13C/15N labeled DNA as sensitive probes of the sugar-backbone conformation in DNA excited states. The chem. shifts, combined with structure-based predictions using an automated fragmentation quantum mechanics/mol. mechanics method, show that the dynamic ensemble of DNA duplexes contg.m1A-T Hoogsteen bps accurately model the excited state Hoogsteen conformation in two different sequence contexts. Formation of excited state A-T Hoogsteen bps is accompanied by changes in sugar-backbone conformation that allow the flipped syn adenine to form hydrogen-bonds with its partner thymine and this in turn results in overall kinking of the DNA toward the major groove. Results support the assignment of Hoogsteen bps as the excited state obsd. in canonical duplex DNA, provide an at. view of DNA dynamics linked to formation of Hoogsteen bps, and lay the groundwork for a potentially general strategy for solving structures of nucleic acid excited states.
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    Quinn, J. R.; Zimmerman, S. C.; Del Bene, J. E.; Shavitt, I. Does the A·T or G·C Base-Pair Possess Enhanced Stability? Quantifying the Effects of CH···O Interactions and Secondary Interactions on Base-Pair Stability Using a Phenomenological Analysis and ab Initio Calculations. J. Am. Chem. Soc. 2007, 129, 934– 941,  DOI: 10.1021/ja066341f
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    Does the A·T or G·C Base-Pair Possess Enhanced Stability? Quantifying the Effects of CH···O Interactions and Secondary Interactions on Base-Pair Stability Using a Phenomenological Analysis and ab Initio Calculations
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    Journal of the American Chemical Society (2007), 129 (4), 934-941CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    An empirically based relationship between overall complex stability (-ΔG°) and various possible component interactions is developed to probe the question of whether the A·T/U and G·C base-pairs exhibit enhanced stability relative to similarly hydrogen-bonded complexes. This phenomenol. approach suggests ∼2-2.5 kcal mol-1 in addnl. stability for A·T owing to a group interaction contg. a CH···O contact. Pairing geometry and the role of the CH···O interaction in the A·T base-pair were also probed using MP2/6-31+G(d,p) calcns. and a double mutant cycle. The ab initio studies indicated that Hoogsteen geometry is preferred over Watson-Crick geometry in A·T by ∼1 kcal mol-1. Factors that might contribute to the preference for Hoogsteen geometry are a shorter CH···O contact, a favorable alignment of dipoles, and greater distances between secondary repulsive sites. The CH···O interaction was also investigated in model complexes of adenine with ketene and isocyanic acid. The ab initio calcns. support the result of the phenomenol. approach that the A·T base-pair does have enhanced stability relative to hydrogen-bonded complexes with just N-H···N and N-H···O hydrogen bonds.
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    Yurenko, Y. P.; Zhurakivsky, R. O.; Samijlenko, S. P.; Hovorun, D. M. Intramolecular CH...O Hydrogen Bonds in the AI and BI DNA-like Conformers of Canonical Nucleosides and their Watson-Crick Pairs. Quantum Chemical and AIM Analysis. J. Biomol. Struct. Dyn. 2011, 29, 51– 65,  DOI: 10.1080/07391102.2011.10507374
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    Intramolecular CH···O hydrogen bonds in the AI and BI DNA-like conformers of canonical nucleosides and their Watson-Crick pairs. Quantum chemical and AIM analysis
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    Journal of Biomolecular Structure and Dynamics (2011), 29 (1), 51-65CODEN: JBSDD6; ISSN:0739-1102. (Adenine Press)
    The aim of this work is to cast some light on the H-bonds in double-stranded DNA in its AI and BI forms. For this purpose, the authors have performed the MP2 and DFT quantum chem. calcns. of the canonical nucleoside conformers, relative to the AI and BI DNA forms, and their Watson-Crick pairs, which were regarded as the simplest models of the double-stranded DNA. Based on the atoms-in-mols. anal. (AIM), five types of the CH···O hydrogen bonds, involving bases and sugar, were detected numerically from 1 to 3 per a conformer: C2'H···O5', C1'H···O2, C6H···O5', C8H···O5', and C6H···O4'. The energy values of H-bonds occupy the range of 2.3-5.6 kcal/mol, surely exceeding the kT value (0.62 kcal/mol). The nucleoside CH···O hydrogen bonds appeared to "survive" turns of bases against the sugar, sometimes in rather large ranges of the angle χ values, pertinent to certain conformations, which points out to the source of the DNA lability, necessary for the conformational adaptation in processes of its functioning. The calcn. of the interactions in the dA·T nucleoside pair gives evidence, that addnl. to the N6H···O4 and N1···N3H canonical H-bonds, between the bases adenine and thymine the third one (C2H···O2) is formed, which, though being rather weak (∼1 kcal/mol), satisfies the AIM criteria of H-bonding and may be classified as a true H-bond. The total energy of all the CH···O nontraditional intramol. H-bonds in DNA nucleoside pairs appeared to be commensurable with the energy of H-bonds between the bases in Watson-Crick pairs, which implies their possible important role in the DNA shaping.
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    Investigation of solvent effect on adenine-thymine base pair interaction
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    In this research, the nature and properties of hydrogen bond interactions in adenine-thymine complex have been investigated using d. functional (B3LYP and M06-2X) and perturbative (MP2) methods. All calcns. have been carried out by the aug-cc-pVDZ basis set. The existence and nature of the weak C-H... O hydrogen bond, in adenine-thymine complex in the gas phase and different solvents, have been investigated. As the solvent effect, the correlation between atoms in mols. (AIM) parameters and geometrical properties of the considered complex have been studied. In addn., solvent effect on the frontier orbital energies, hardness and dipole moment of adenine-thymine complex have been investigated.
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    Gatti, C.; Macetti, G.; Boyd, R. J.; Matta, C. F. An Electron Density Source-Function Study of DNA Base Pairs in Their Neutral and Ionized Ground States†. J. Comput. Chem. 2018, 39, 1112– 1128,  DOI: 10.1002/jcc.25222
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    An electron density source-function study of DNA base pairs in their neutral and ionized ground states
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    Journal of Computational Chemistry (2018), 39 (18), 1112-1128CODEN: JCCHDD; ISSN:0192-8651. (John Wiley & Sons, Inc.)
    The source function (SF) decomps. the electron d. at any point into contributions from all other points in the mol., complex, or crystal. The SF "illuminates" those regions in a mol. that most contribute to the electron d. at a point of ref. When this point of ref. is the bond crit. point (BCP), a commonly used surrogate of chem. bonding, then the SF anal. at an at. resoln. within the framework of Bader's Quantum Theory of Atoms in Mols. returns the contribution of each atom in the system to the electron d. at that BCP. The SF is used to locate the important regions that control the H-bonds in both Watson-Crick (WC) DNA dimers [adenine:thymine (A-T) and guanine:cytosine (G-C)] which were studied in their neutral and their singly ionized (radical cationic and anionic) ground states. The at. contributions to the electron d. at the BCPs of the H-bonds in the 2 dimers were found to be delocalized to various extents. Surprisingly, gaining or loosing an electron had similar net effects on some H-bonds concealing subtle compensations traced to at. sources contributions. Coarser levels of resolns. (groups, rings, and/or monomers-in-dimers) revealed that distant groups and rings often had non-negligible effects, esp. on the weaker H-bonds such as the 3rd weak C-H...O H-bond in A-T. Interestingly, neither the purine nor the pyrimidine in the neutral or ionized forms dominated any given H-bond despite that the former had more atoms that could act as a source or sink for the d. at its BCP.
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    Sugiyama, T.; Schweinberger, E.; Kazimierczuk, Z.; Ramzaeva, N.; Rosemeyer, H.; Seela, F. 2-Aza-2′-deoxyadenosine: Synthesis, Base-Pairing Selectivity, and Stacking Properties of Oligonucleotides. Chem. - Eur. J. 2000, 6, 369– 378,  DOI: 10.1002/(SICI)1521-3765(20000117)6:2<369::AID-CHEM369>3.0.CO;2-2
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    2-Aza-2'-deoxyadenosine: synthesis, base-pairing selectivity, and stacking properties of oligonucleotides
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    Chemistry - A European Journal (2000), 6 (2), 369-378CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH)
    2-Aza-2'-deoxyadenosine (z2Ad) is synthesized via its 1,N6-etheno deriv. and enzymically deaminated to 2-aza-2'-deoxyinosine. 2-Aza-2'-deoxyadenosine is converted into the phosphoramidite building block. This is employed in solid-phase oligonucleotide synthesis. The 2-azapurine base forms a strong base pair with guanine, but a much weaker one with adenine, thymine, and cytosine. Oligonucleotide duplexes with dangling nucleotide residues, such as 2-aza-2'-deoxyadenosine and 7-deaza-2'-deoxyadenosine (c7Ad), either on one or both termini, are synthesized, and the thermal stability of the duplexes is correlated with the hydrophobic properties of the dangling nucleotide residues.
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    Nguyen, B.; Neidle, S.; Wilson, W. D. A Role for Water Molecules in DNA–Ligand Minor Groove Recognition. Acc. Chem. Res. 2009, 42, 11– 21,  DOI: 10.1021/ar800016q
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    A Role for Water Molecules in DNA-Ligand Minor Groove Recognition
    Nguyen, Binh; Neidle, Stephen; Wilson, W. David
    Accounts of Chemical Research (2009), 42 (1), 11-21CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
    A review. Targeting the minor groove of DNA through binding to a small mol. has long been considered an important mol.-recognition strategy in biol. A wide range of synthetic heterocyclic mols. bind noncovalently in the minor groove of the double helix and are also effective against a no. of human and animal diseases. A classic structural concept, the isohelicity principle, has guided much of this work: such heterocyclic mols. require a shape that complements the convex surface of the minor groove. Researchers have used this principle to design mols. that can read DNA sequences. This principle also predicts that mols. that lack the complementary shape requirement would only bind weakly to DNA. Recently, however, researchers have unexpectedly found that some essentially linear compds., which do not have this feature, can have high DNA affinity. In this Account, we discuss an alternative recognition concept based on these new findings. We demonstrate that highly structured water mols. can play a key role in mediating between the ligand and DNA minor groove without loss of binding affinity. Combined structural and thermodn. approaches to understanding the behavior of these mols. have shown that there are different categories of bound water in their DNA complexes. For example, application of this water-bridging concept to the phenylamidine platform has resulted in the discovery of mols. with high levels of biol. activity and low nonspecific toxicity. Some of these mols. are now in advanced clin. trials.
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    Jóhannesson, H.; Halle, B. Minor Groove Hydration of DNA in Solution: Dependence on Base Composition and Sequence. J. Am. Chem. Soc. 1998, 120, 6859– 6870,  DOI: 10.1021/ja974316r
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    Minor Groove Hydration of DNA in Solution: Dependence on Base Composition and Sequence
    Johannesson, Haukur; Halle, Bertil
    Journal of the American Chemical Society (1998), 120 (28), 6859-6870CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The hydration of six B-DNA dodecamers with A-tracts of variable length and sequence has been investigated via the nuclear magnetic relaxation dispersion (NMRD) of the water 2H and 17O resonances. By subdividing the aq. DNA soln. into microscopic emulsion droplets, NMRD measurements could be performed at -20°, thereby greatly enhancing the sensitivity of the method. The NMRD profiles show that all six dodecamers contain long-lived water mols. These water mols. are displaced by netropsin and must therefore be located in the minor groove. The no. of long-lived water mols. is correlated with the width of the minor groove as seen in crystal structures. The NMRD data are consistent with a single file of 3-9 long-lived water mols. located at the base pair steps and extending 1-2 steps on either side of the A-tract. Dodecamers with central A-tracts of sequence A4T4, T4A4, and (AT)4 are found to contain seven or nine long-lived water mols., challenging the common view that T-A steps widen the minor groove and disrupt the hydration structure. The long-lived water mols. obsd. here are highly ordered with an entropy comparable to that of water mols. in ice, but most of them undergo a sym. flip motion while residing in the groove. The mean water residence time is essentially the same, 10-15 ns at -20°, for all investigated dodecamers, suggesting that water exchange occurs from an open state with a uniformly wide minor groove. From the temp. dependence of the water residence time, an activation enthalpy of 53 kJ mol-1 is obtained for this process.
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    Verma, S. D.; Pal, N.; Singh, M. K.; Sen, S. Sequence-Dependent Solvation Dynamics of Minor-Groove Bound Ligand Inside Duplex-DNA. J. Phys. Chem. B 2015, 119, 11019– 11029,  DOI: 10.1021/acs.jpcb.5b01977
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    Sequence-Dependent Solvation Dynamics of Minor-Groove Bound Ligand Inside Duplex-DNA
    Verma, Sachin Dev; Pal, Nibedita; Singh, Moirangthem Kiran; Sen, Sobhan
    Journal of Physical Chemistry B (2015), 119 (34), 11019-11029CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
    Ligand binding to minor-grooves of DNA depends on DNA-base sequence near its binding-site. However, it is not known how base-sequences affect the local solvation of ligand inside minor-grooves of DNA. Here we present a comprehensive study on sequence-dependent solvation dynamics of ligand inside duplex-DNA by measuring the static and dynamic fluorescence Stokes shifts of a popular groove-binder, DAPI, inside DNA minor-grooves created by four different sequences; d(5'-CGCGAATTCGCG-3')2, d(5'-CGCGTTAACGCG-3')2, d(5'-CGCGCAATTGCGCG-3')2, and d(5'-CGCGCTTAAGCGCG-3')2, having different sequences near DAPI-binding site. Fluorescence up-conversion and time-correlated single photon counting techniques are employed to capture the dynamic Stokes shifts of DAPI over five decades in time from 100 fs to 10 ns. We show that the ligands sense different static and dynamic solvation inside minor-grooves created by different sequences: Only subtle change in the dynamics is seen in DNA contg. -AATTG-, -TTAAG-, and -AATTC- sequences, which show power-law relaxation in initial time-decades, followed by biexponential decay in nanosecond time-scales. However, changing a single base (and the complementary base) near ligand-binding site from -TTAAG- to -TTAAC- drastically induces the dynamics to follow a single power-law relaxation over the entire five decades. The obsd. variation of dynamics possibly relate to the local DNA motions, coupled to the hydration dynamics near the ligand-binding site.
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This article is cited by 8 publications.

  1. Claudia G. Giribet. IPPP–CLOPPA Analysis of the Hydrogen Bonds of the Adenine–Thymine Base Pair. Is C–H···O the Third Hydrogen Bond?. The Journal of Physical Chemistry A 2024, 128 (36) , 7568-7580. https://doi.org/10.1021/acs.jpca.4c03817
  2. Hao-Che Peng, Shrijaa Mohan, Muhammad T. Huq, Julie A. Bull, Troy Michaud, Turner C. Piercy, Stefan Hilber, Ashan P. Wettasinghe, Jason D. Slinker, Christoph Kreutz, Allison L. Stelling. Isotope-Edited Variable Temperature Infrared Spectroscopy for Measuring Transition Temperatures of Single A-T Watson–Crick Base Pairs in DNA Duplexes. Analytical Chemistry 2024, 96 (22) , 8868-8874. https://doi.org/10.1021/acs.analchem.4c00056
  3. Chi H. Mak. Hydration Waters Make Up for the Missing Third Hydrogen Bond in the A·T Base Pair. ACS Physical Chemistry Au 2024, 4 (2) , 180-190. https://doi.org/10.1021/acsphyschemau.3c00058
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  5. Wenting Meng, Hao-Che Peng, Yuanhao Liu, Allison Stelling, Lu Wang. Modeling the Infrared Spectroscopy of Oligonucleotides with 13C Isotope Labels. The Journal of Physical Chemistry B 2023, 127 (11) , 2351-2361. https://doi.org/10.1021/acs.jpcb.2c08915
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Cite this: J. Phys. Chem. B 2021, 125, 28, 7613–7627
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https://doi.org/10.1021/acs.jpcb.1c01351
Published July 8, 2021

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  • Abstract

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    Figure 1

    Figure 1. CH···O H-bonding in A–T DNA base pairs. (A) Potential, third CH···O H-bond in Watson–Crick and (B) Hoogsteen A–T DNA base pairs. (C) Typically used geometric definition for CH···O H-bonds.

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    Figure 2

    Figure 2. Isotope editing and spectral subtraction isolate isotope signals from individual T bases in DNA duplexes. (A) In isotope editing experiments, an isotopically labeled base is site-specifically incorporated into a DNA duplex (heavy, blue) and the heavy IR spectrum is subtracted from the IR spectrum of a light duplex (black), which has an identical sequence. In the “light–heavy” subtraction spectrum, signals due to the light 12C═O appear as positive bands, and signals due to the heavy 13C═O appear as negative bands. Signals that arise from vibrations in which the C2 atom does not participate are canceled out, thus reducing spectral congestion so that C═O stretching of a specific bond of an individual DNA base can be observed in the duplex environment. (B) B-form DNA duplex illustrating the local environment of a TC2═O bond. Arrows indicate nearby functional groups on neighboring bases that may impact the stretching frequency. Distances are in angstrom.

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    Scheme 1

    Scheme 1. Synthesis of 2-13C-Labeled Thymidine Phosphoramiditea
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    a(a) Acetic anhydride, 90 °C, 1 h, and 81%; (b) Pd/BaSO4 5%, H2, in AcOH/H2O, 16 h, rt, and 67%; (c) 1. HMDS, TMS-Cl, 120 °C, 16 h, then Hoffer′s α-chlorosugar, in CHCl3, 4 h, 40 °C, and 56%; (d) CH3NH2 in EtOH 8 M, 16 h, RT, and 88%; (e) DMT-Cl, DMAP, in pyridine, 3 h, rt, and 71%; and (f) CEP-Cl, DIPEA, in CH2Cl2, RT, 3 h, and 74%. DMT, 4,4′-dimethoxytrityl and CEP, 3′-O-(N,N-diisopropyl phosphoramidite).

    Figure 3

    Figure 3. Isotope editing experiments pinpoint TC2═O IR signals in Watson–Crick base pairs in DNA duplexes. The sequence of the palindromes TA-DNA (A) and AT-DNA (B). Labeled T bases are indicated in red. (C) Light minus heavy IR difference spectrum of 13C2-labeled TA-DNA (black) and AT-DNA (green). Positive bands from 12C2═O and negative bands from 13C2═O are labeled. (D) Enhanced view of the carbonyl region in (C) showing splitting in the minor signal of the AT-DNA duplex. A representative noise line (replicate minus replicate for TA-DNA) is shown in red. The mean of four independent measurements is shown in bold, and the standard deviation in shade.

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    Figure 4

    Figure 4. Isolation of the TC2═O stretching signal in a DNA/drug complex with Hoogsteen base pairs. (A) Chemical structure of echinomycin (magenta) and a crystal structure of the bound TA-DNA (PDBID: 1XVN), (91) which induces the formation of two Hoogsteen base pairs (blue). Dashes indicate functional groups from echinomycin close to the labeled carbonyls (distances in angstrom). (B) and (C) GC-step binding sites of echinomycin in TA-DNA are boxed (magenta). Echinomycin was bound to both the light and heavy TA-DNA duplexes and their difference spectra calculated to isolate signals from the two A–T Hoogsteen (T6/T18, blue box) base pairs’ TC2═O stretching signals (see the chemical structure; TC2═O is in red). (D) and (E) Light minus heavy IR difference spectrum of the 13C2-labeled DNA/echinomycin complex with the positive signals from the light isotope labeled. Representative noise lines (replicate minus replicate) are shown in red. The mean of three to four independent measurements is shown in bold, and the standard deviation in shade.

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    Figure 5

    Figure 5. Isotope editing pinpoints a single T atom in two DNA duplexes. (A) Sequence of A6-DNA with the labeled T (T9) in red. (B) Chemical structure of N1-methyladenine (m1A) incorporated at A16, opposite the 13C2-labeled T (red). Methyl group on the adenine N1 has a steric clash with the T N3–H, resulting in the purine flipping over into its Hoogsteen form. (C) Light minus heavy difference spectra of A6-DNA (black) and m1A-A6-DNA (blue).

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    Figure 6

    Figure 6. Acceptor numbers for A–T base pairs in DNA duplexes. A plot of the solvent’s Gutmann H-bond acceptor number (AN) vs the observed TC2═O stretching. Values for 13C2-labeled duplexes, the Hoogsteen crystal, and the isolated matrix N1-methylthymine were calculated based on the regression line derived from the observed values for the T base in water, dimethylformamide (DMF), and d6-dimethyl sulfoxide (d6-DMSO). The isolated matrix value is from N1-methylthymine in the study by Person and co-workers. (112)

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  • References

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      This lab. expt. allows one to study the effect of temp. in the process of formation of hydrogen bound cyclic dimers of benzoic acid (BA). The implementation of the proposed methodol., which comprises the use of FTIR spectroscopy and quantum chem. calcns., enables the obtaining of the thermodn. parameters of the dimerization reaction and their subsequent validation by computational chem. calcns. Hence, the students are involved in a practical learning scheme focused in the study of a central topic in chem., such as hydrogen bonding, with the final purpose being to train chem. students in applying theor.-exptl. approaches to ext. meaningful data and valuable information for explaining exptl. observables.
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      Ester Carbonyl Vibration as a Sensitive Probe of Protein Local Electric Field
      Pazos, Ileana M.; Ghosh, Ayanjeet; Tucker, Matthew J.; Gai, Feng
      Angewandte Chemie, International Edition (2014), 53 (24), 6080-6084CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      The ability to quantify the local electrostatic environment of proteins and protein/peptide assemblies is key to gaining a microscopic understanding of many biol. interactions and processes. Herein, we show that the ester carbonyl stretching vibration of two non-natural amino acids, L-aspartic acid 4-Me ester and L-glutamic acid 5-Me ester, is a convenient and sensitive probe in this regard, since its frequency correlates linearly with the local electrostatic field for both hydrogen-bonding and non-hydrogen-bonding environments. We expect that the resultant frequency-elec.-field map will find use in various applications. Furthermore, we show that, when situated in a non-hydrogen-bonding environment, this probe can also be used to measure the local dielec. const. (ε). For example, its application to amyloid fibrils formed by Aβ16-22 revealed that the interior of such β-sheet assemblies has an ε value of approx. 5.6.
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    13. 13
      Deng, H. Chapter Five - Enzyme Active Site Interactions by Raman/FTIR, NMR, and Ab Initio Calculations. In Advances in Protein Chemistry and Structural Biology, Christov, C. Z., Ed.; Academic Press, 2013; Vol. 93, pp 153– 182.
      There is no corresponding record for this reference.
    14. 14
      Schneider, S. H.; Boxer, S. G. Vibrational Stark Effects of Carbonyl Probes Applied to Reinterpret IR and Raman Data for Enzyme Inhibitors in Terms of Electric Fields at the Active Site. J. Phys. Chem. B 2016, 120, 9672– 9684,  DOI: 10.1021/acs.jpcb.6b08133
      14
      Vibrational Stark Effects of Carbonyl Probes Applied to Reinterpret IR and Raman Data for Enzyme Inhibitors in Terms of Electric Fields at the Active Site
      Schneider, Samuel H.; Boxer, Steven G.
      Journal of Physical Chemistry B (2016), 120 (36), 9672-9684CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      IR and Raman frequency shifts have been reported for numerous probes of enzyme transition states, leading to diverse interpretations. In the case of the model enzyme, ketosteroid isomerase (KSI), the authors have previously argued that IR spectral shifts for a carbonyl probe at the active site can provide a connection between the active site elec. field and the activation free energy. Here, the authors generalized this approach to a much broader set of carbonyl probes (e.g., oxoesters, thioesters, and amides), 1st establishing the sensitivity of each probe to an elec. field using vibrational Stark spectroscopy, vibrational solvatochromism, and mol. dynamics simulations, and then applying these results to re-interpret data already in the literature for enzymes such as 4-chlorobenzoyl-CoA dehalogenase and serine proteases such as chymotrypsin and subtilisin BPN' and Carlsberg. These results demonstrated that the vibrational Stark effect provides a general framework for estg. the electrostatic contribution to the catalytic rate and may provide a metric for the design or modification of enzymes. Opportunities and limitations of the approach are also described.
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    15. 15
      Tonge, P. J.; Carey, P. R. Length of the acyl carbonyl bond in acyl-serine proteases correlates with reactivity. Biochemistry 1990, 29, 10723– 10727,  DOI: 10.1021/bi00500a002
      15
      Length of the acyl carbonyl bond in acyl-serine proteases correlates with reactivity
      Tonge, Peter J.; Carey, Paul R.
      Biochemistry (1990), 29 (48), 10723-7CODEN: BICHAW; ISSN:0006-2960.
      Resonance Raman (RR) spectroscopy was used to obtain the vibrational spectrum of the acyl carbonyl group in a series of acylchymotrypsins and acylsubtilisins at the pH of optimum hydrolysis. The acyl-enzymes, which utilized (arylacryloyl) acyl groups, included 3 oxyanion hole mutants of subtilisin BPN', Asn-155 → Leu, Asn-155 → Gln, and Asn-155 → Arg, and encompassed a 500-fold range of deacylation rate consts. For each acyl-enzyme, a RR carbonyl band was identified that arose from a population of carbonyl groups undergoing nucleophilic attack in the active site. As the deacylation rate (k3) increased through the series of acyl-enzymes, the carbonyl stretching band (νC:O) was obsd. to shift to lower frequency, indicating an increase in the single bond character of the reactive acyl carbonyl group. Expts. involving the oxyanion hole mutants of subtilisin BPN' indicated that a shift of νC:O to lower frequency resulted from stronger H-bonding of the acyl carbonyl group in the oxyanion hole. A plot of log k3 against νC:O was linear over the range investigated, demonstrating that the changes in νC:O correlated with the free energy of activation for the deacylation reaction. By use of an empirical correlation between carbonyl frequency (νC:O) and carbonyl bond length (rC:O), it was estd. that rC:O increased by 0.015 Å as the deacylation rate increased 500-fold through the series of acyl-enzymes. This change in rC:O was ∼7% of that expected for going from a formal C:O double bond in the acyl-enzyme to a formal C-O single bond in the tetrahedral intermediate for deacylation. The data also allowed estn. of the energy needed to extend the acyl carbonyl group along its axis as 950 kJ/mol/Å.
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    16. 16
      Tonge, P. J.; Carey, P. R. Forces, bond lengths, and reactivity: fundamental insight into the mechanism of enzyme catalysis. Biochemistry 1992, 31, 9122– 9125,  DOI: 10.1021/bi00153a002
      16
      Forces, bond lengths, and reactivity: fundamental insight into the mechanism of enzyme catalysis
      Tonge, Peter J.; Carey, Paul R.
      Biochemistry (1992), 31 (38), 9122-5CODEN: BICHAW; ISSN:0006-2960.
      Comparison of spectroscopic, kinetic, and thermodn. data for a series of functioning acyl-serine proteases suggests that the obsd. variation in deacylation rates can be accounted for by changes in the properties of the acyl-enzyme's ground state. The acyl-enzyme's catalytically crucial acyl carbonyl group is probed by resonance Raman spectroscopy. Its spectral frequency is used to gauge both the carbonyl bond length and the strength of hydrogen bonding (originating from groups making up the oxyanion hole) to the carbonyl oxygen atom. As the deacylation rate increases 16,300-fold through the series, a shift in carbonyl frequency, νC=O, of -54 cm-1 corresponds to a carbonyl bond length increase of 0.025 Å. The decrease in νC=O is also consistent with an increase in hydrogen bond donor enthalpy of -27 kJ mol-1. Interestingly, this value resembles closely the decrease in activation energy for deacylation through the series, 24 kJ mol-1, demonstrating that the hydrogen bonds to the carbonyl oxygen atom can provide sufficient energy to account for the obsd. rate accelerations.
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    17. 17
      Tonge, P. J.; Fausto, R.; Carey, P. R. FTIR studies of hydrogen bonding between α,β-unsaturated esters and alcohols. J. Mol. Struct. 1996, 379, 135– 142,  DOI: 10.1016/0022-2860(95)09117-3
      17
      FTIR studies of hydrogen bonding between α,β-unsaturated esters and alcohols
      Tonge, P. J.; Fausto, R.; Carey, P. R.
      Journal of Molecular Structure (1996), 379 (), 135-142CODEN: JMOSB4; ISSN:0022-2860. (Elsevier)
      The enthalpy (and entropy) of hydrogen bond formation has been measured between the ester carbonyl groups of the two α,β-unsatd. esters thienylacryloyl (TAOMe) and 5-methylthienylacryloyl (5MeTAOMe) Me ester and the hydrogen bond donors ethanol, phenol and 3,5-dichlorophenol in CCl4. For the esters, the hydrogen bonding strengths were measured by quantitating the amt. of bound and unbound donor, using the O-H stretching region, as a function of temp. and applying the van't Hoff equation. The decrease in νC:O of the ester carbonyl group upon hydrogen bond formation (ΔνC:O) has also been measured and correlated with the enthalpy of hydrogen bond formation. A linear correlation is obsd. between the enthalpy of hydrogen bond formation -ΔH and ΔνC:O, with -ΔH = 1.36ΔνC:O-16.1, where ΔH is measured in kJ mol-1 and Δν in cm-1. Comparison with data for other carbonyl acceptor compds. indicates that the carbonyl group of the above α,β-unsatd. esters is more readily polarized than the carbonyl group of satd. esters or ketones. The quant. relationship between -ΔH and ΔνC:O derived here has been used to det. the change in the enthalpy of hydrogen bond formation between substrate and enzyme groups in a series of acylserine proteases.
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    18. 18
      Latajka, Z.; Scheiner, S. Correlation between interaction energy and shift of the carbonyl stretching frequency. Chem. Phys. Lett. 1990, 174, 179– 184,  DOI: 10.1016/0009-2614(90)80103-K
      18
      Correlation between interaction energy and shift of the carbonyl stretching frequency
      Latajka, Zdzislaw; Scheiner, Steve
      Chemical Physics Letters (1990), 174 (2), 179-84CODEN: CHPLBC; ISSN:0009-2614.
      The shift in the C = O stretching frequency of H2CO, when interacting with Na+, Mg2+, H+, H3O+,and H2O, fits a linear correlation with the computed interaction energy. The slope of this line is such that 1 kcal mol-1 in ΔE is assocd. with a frequency decrease of 2 cm-1.
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    19. 19
      Banyay, M.; Sarkar, M.; Gräslund, A. A library of IR bands of nucleic acids in solution. Biophys. Chem. 2003, 104, 477– 488,  DOI: 10.1016/S0301-4622(03)00035-8
      19
      A library of IR bands of nucleic acids in solution
      Banyay, Martina; Sarkar, Munna; Graslund, Astrid
      Biophysical Chemistry (2003), 104 (2), 477-488CODEN: BICIAZ; ISSN:0301-4622. (Elsevier Science B.V.)
      A review. This review presents a compilation and discussion of IR bands characteristic of nucleic acids in various conformations. The entire spectral range 1800-800 cm-1 relevant for DNA/RNA in aq. soln. has been subdivided into four sections. Each section contains descriptions of bands appearing from group specific parts of nucleic acid structure, such as nucleobase, base-sugar, sugar-phosphate and sugar moiety. The approach allows comparisons of information obtained from one spectral region with another. The IR band library should facilitate detailed and unambiguous assignment of structural changes, ligand binding, etc. in nucleic acids from IR spectra. is aimed at highlighting specific features that are useful for following major changes in nucleic acid structures. also concerns some recent results, where IR spectroscopy has been used to obtain semi-quant. information on coexisting modes of sugar pucker in oligonucleotides.
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    20. 20
      Menssen, R. J.; Tokmakoff, A. Length-Dependent Melting Kinetics of Short DNA Oligonucleotides Using Temperature-Jump IR Spectroscopy. J. Phys. Chem. B 2019, 123, 756– 767,  DOI: 10.1021/acs.jpcb.8b09487
      20
      Length-dependent melting kinetics of short DNA oligonucleotides using temperature-jump IR spectroscopy
      Menssen, Ryan J.; Tokmakoff, Andrei
      Journal of Physical Chemistry B (2019), 123 (4), 756-767CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      In this work, we utilized FTIR and temp.-jump (T-jump) IR spectroscopy to investigate the melting thermodn. and kinetics of a series of 5 DNA sequences ranging from 6 to 14 base pairs long. IR spectroscopy is well suited for the study of DNA because of its ability to distinguish base-specific information, and the nanosecond time resoln. of the T-jump app. can access the relevant range of kinetics. Eyring anal. of a 2-state model examd. both the activation enthalpy and entropy, providing new insights into the energetic driving forces and phys. processes behind the assocn. and dissocn. while also helping to clarify the commonly obsd. neg. activation energy. Global anal. of the thermodn. and kinetic data applying a linear dependence of activation barriers on oligo length provides a holistic result by producing reasonable agreement between our data and existing nearest-neighbor (NN) thermodn. parameters blending the exptl. results with established predictive models. By studying the trends in the thermodn. and kinetics as a function of length, this work demonstrated a direct correlation between the effects addnl. dinucleotides have on the kinetics and the NN parameters for those dinucleotides. This result further supports the development of a kinetic analog to the thermodn. NN parameters.
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    21. 21
      Ashwood, B.; Sanstead, P. J.; Dai, Q.; He, C.; Tokmakoff, A. 5-Carboxylcytosine and Cytosine Protonation Distinctly Alter the Stability and Dehybridization Dynamics of the DNA Duplex. J. Phys. Chem. B 2020, 124, 627– 640,  DOI: 10.1021/acs.jpcb.9b11510
      21
      5-Carboxylcytosine and cytosine protonation distinctly alter the stability and dehybridization dynamics of the DNA duplex
      Ashwood, Brennan; Sanstead, Paul J.; Dai, Qing; He, Chuan; Tokmakoff, Andrei
      Journal of Physical Chemistry B (2020), 124 (4), 627-640CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Applications assocd. with nucleobase protonation events are grounded in their fundamental impact on DNA thermodn., structure, and hybridization dynamics. Of the canonical nucleobases, N3 protonation of cytosine (C) is the most widely utilized in both biol. and nanotechnol. Naturally occurring C derivs. that shift the N3 pKa introduce an addnl. level of tunability. The epigenetic nucleobase 5-carboxylcytosine (caC) presents a particularly interesting example since this deriv. forms Watson-Crick base pairs of similar stability and displays pH-dependent behavior over the same range as the canonical nucleobase. However, the titratable group in caC corresponds to the exocyclic carboxyl group rather than N3, and the implications of these divergent protonation events toward DNA hybridization thermodn., kinetics, and base pairing dynamics remain poorly understood. Here, we study the pH dependence of these phys. properties using model oligonucleotides contg. C and caC with FTIR and temp.-jump IR spectroscopy. We demonstrate that N3 protonation of C completely disrupts duplex stability, leading to large shifts in the duplex/single-strand equil., a redn. in the cooperativity of melting, and an acceleration in the rate of duplex dissocn. In contrast, while increasing 5-carboxyl protonation in caC-contg. duplexes induces an increase in base pair fluctuations, the DNA duplex can tolerate substantial protonation without significant perturbation to the duplex/single-strand equil. However, 5-carboxyl protonation has a large impact on hybridization kinetics by reducing the transition state free energy. Our thermodn. and kinetic anal. provides new insight on the impact of two divergent protonation mechanisms in naturally occurring nucleobases on the biophys. properties of DNA.
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    22. 22
      Wood, B. R. The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues. Chem. Soc. Rev. 2016, 45, 1980– 1998,  DOI: 10.1039/C5CS00511F
      22
      The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues
      Wood, Bayden R.
      Chemical Society Reviews (2016), 45 (7), 1980-1998CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
      Since Watson and Crick's historical papers on the structure and function of DNA based on Rosalind Franklin's and Maurice Wilkin's X-ray diffraction patterns tremendous scientific curiosity has been aroused by the unique and dynamic structure of the mol. of life. A-DNA and B-DNA represent different conformations of the DNA mol., which is stabilized by hydrogen interactions between base pairs, stacking interactions between neighboring bases and long-range intra- and inter-backbone forces. This review highlights the contribution Fourier transform IR (FTIR) spectroscopy has made to the understanding of DNA conformation in relation to hydration and its potential role in clin. diagnostics. The review will first begin by elucidating the main forms of DNA conformation found in nature and the general structures of the A, B and Z forms. This is followed by a detailed critique on IR spectroscopy applied to DNA conformation highlighting pivotal studies on isolated DNA, polynucleotides, nucleoprotein and nucleohistone complexes. A discussion on the potential of diagnosing cancer using FTIR spectroscopy based on the detection of DNA bands in cells and tissues will ensue, highlighting the recent studies investigating the conformation of DNA in hydrated and dehydrated cells. The method of hydration as a way to facilitate DNA conformational band assignment will be discussed and the conformational change to the A-form upon dehydration will be used to explain the reason for the apparent lack of FTIR DNA signals obsd. in fixed or air-dried cells and tissues. The advantages of investigating B-DNA in the hydrated state, as opposed to A-DNA in the dehydrated state, are exemplified in a series of studies that show: (1) improved quantification of DNA in cells; (2) improved discrimination and reproducibility of FTIR spectra recorded of cells progressing through the cell cycle; (3) insights into the biol. significance of A-DNA as evidenced by an interesting study on bacteria, which can survive desiccation and at the same time undergo the B-A-B transition. Finally, the importance of preserving the B-DNA conformation for the diagnosis of cancer is put forward as way to improve the sensitivity of this powerful technique.
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    23. 23
      Hithell, G.; Ramakers, L. A. I.; Burley, G. A.; Hunt, N. T. Applications of 2D-IR Spectroscopy to Probe the Structural Dynamics of DNA. In Frontiers and Advances in Molecular Spectroscopy, Laane, J., Ed.; Elsevier, 2018; Chapter 3, pp 77– 100.
      There is no corresponding record for this reference.
    24. 24
      Hithell, G.; Shaw, D. J.; Donaldson, P. M.; Greetham, G. M.; Towrie, M.; Burley, G. A.; Parker, A. W.; Hunt, N. T. Long-Range Vibrational Dynamics Are Directed by Watson–Crick Base Pairing in Duplex DNA. J. Phys. Chem. B 2016, 120, 4009– 4018,  DOI: 10.1021/acs.jpcb.6b02112
      24
      Long-Range Vibrational Dynamics Are Directed by Watson-Crick Base Pairing in Duplex DNA
      Hithell, Gordon; Shaw, Daniel J.; Donaldson, Paul M.; Greetham, Gregory M.; Towrie, Michael; Burley, Glenn A.; Parker, Anthony W.; Hunt, Neil T.
      Journal of Physical Chemistry B (2016), 120 (17), 4009-4018CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Ultrafast two-dimensional IR (2D-IR) spectroscopy of a 15-mer A-T DNA duplex in soln. has revealed structure-dependent vibrational coupling and energy transfer processes linking bases with the sugar-phosphate backbone. Duplex melting induces significant changes in the positions of off-diagonal peaks linking carbonyl and ring-stretching vibrational modes of the adenine and thymine bases with vibrations of the phosphate group and phosphodiester linkage. These indicate that Watson-Crick hydrogen bonding and helix formation lead to a unique vibrational coupling arrangement of base vibrational modes with those of the phosphate unit. On the basis of observations from time-resolved 2D-IR data, we conclude that rapid energy transfer processes occur between base and backbone, mediated by addnl. modes located on the deoxyribose moiety within the same nucleotide. These relaxation dynamics are insensitive to duplex melting, showing that efficient intramol. energy relaxation to the solvent via the phosphate groups is the key to excess energy dissipation in both single- and double-stranded DNA.
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    25. 25
      Krummel, A. T.; Zanni, M. T. DNA Vibrational Coupling Revealed with Two-Dimensional Infrared Spectroscopy: Insight into Why Vibrational Spectroscopy Is Sensitive to DNA Structure. J. Phys. Chem. B 2006, 110, 13991– 14000,  DOI: 10.1021/jp062597w
      25
      DNA Vibrational Coupling Revealed with Two-Dimensional Infrared Spectroscopy: Insight into Why Vibrational Spectroscopy Is Sensitive to DNA Structure
      Krummel, Amber T.; Zanni, Martin T.
      Journal of Physical Chemistry B (2006), 110 (28), 13991-14000CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      Two-dimensional IR (2D IR) spectroscopy was used to study the carbonyl vibrational modes of guanine and cytosine bases in A- and B-form DNA. Located between 1600 and 1700 cm-1, these modes are often used to monitor DNA secondary structure with traditional IR spectroscopies such as FTIR, but traditional spectroscopies lack the necessary observables to unravel the coupling mechanisms that make these modes sensitive to secondary structure. By using 2D IR spectroscopy and electronic structure calcns. on d(G5C5) and d(GC)8 model nucleic acids, the authors find that hydrogen-bonded guanine/cytosine base pairs are primarily electrostatically coupled and that the coupling between these modes can be modeled with a transition dipole d. approach. In comparison, electrostatics is insufficient to model stacked bases because of cooperative charge-sharing effects, but the coupling can be accurately calcd. using a finite difference method. The authors find that the coupling is very strong for both hydrogen-bonded and stacked base geometries, creating vibrational modes that extend both across the base pairs and along the lengths of the helixes. The authors' results provide a phys. basis for understanding how strong coupling gives rise to the empirically established relation between IR spectroscopy and DNA/RNA secondary structure.
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    26. 26
      Krummel, A. T.; Mukherjee, P.; Zanni, M. T. Inter and Intrastrand Vibrational Coupling in DNA Studied with Heterodyned 2D-IR Spectroscopy. J. Phys. Chem. B 2003, 107, 9165– 9169,  DOI: 10.1021/jp035473h
      26
      Inter and intrastrand vibrational coupling in DNA studied with heterodyned 2D-IR spectroscopy
      Krummel, Amber T.; Mukherjee, Prabuddha; Zanni, Martin T.
      Journal of Physical Chemistry B (2003), 107 (35), 9165-9169CODEN: JPCBFK; ISSN:1520-6106. (American Chemical Society)
      Heterodyned 2D-IR, frequency resolved photon echo, and pump-probe spectroscopies were collected to study the couplings and anharmonicities of cytidine and guanosine bases in DNA. Cytidine and guanosine anharmonicities were measured to be 9 and 14 cm-1, resp. Strong cross-peaks were obsd. between the guanosine (G) and cytosine (C) carbonyl stretches in the 2D-IR spectra of the self-complementary oligonucleotide dG5C5 (5'-GGGGGCCCCC-3'). The spectra are interpreted in terms of inter- and intrastrand couplings between the carbonyl modes, and an excitonic Hamiltonian, based on transition dipole coupling, was used to fit the 2D-IR spectra. The accuracy of this model is discussed in light of obsd. couplings to the ring modes.
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    27. 27
      Zhang, X.-X.; Brantley, S. L.; Corcelli, S. A.; Tokmakoff, A. DNA minor-groove binder Hoechst 33258 destabilizes base-pairing adjacent to its binding site. Commun. Biol. 2020, 3, 525  DOI: 10.1038/s42003-020-01241-4
      27
      DNA minor-groove binder Hoechst 33258 destabilizes base-pairing adjacent to its binding site
      Zhang, Xin-Xing; Brantley, Shelby L.; Corcelli, Steven A.; Tokmakoff, Andrei
      Communications Biology (2020), 3 (1), 525CODEN: CBOIDQ; ISSN:2399-3642. (Nature Research)
      Understanding the dynamic interactions of ligands to DNA is important in DNA-based nanotechnologies. By structurally tracking the dissocn. of Hoechst 33258-bound DNA (d(CGCAAATTTGCG)2) complex (H-DNA) with T-jump 2D-IR spectroscopy, the ligand is found to strongly disturb the stability of the three C:G base pairs adjacent to A:T the binding site, with the broken base pairs being more than triple at 100 ns. The strong stabilization effect of the ligand on DNA duplex makes this observation quite striking, which dramatically increases the melting temp. and dissocn. time. MD simulations demonstrate an important role of hydration water and counter cations in maintaining the sepn. of terminal base pairs. The hydrogen bonds between the ligand and thymine carbonyls are crucial in stabilizing H-DNA, whose breaking signal appearing prior to the complete dissocn. Thermodn. anal. informs us that H-DNA assocn. is a concerted process, where H cooperates with DNA single strands in forming H-DNA.
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    28. 28
      Hithell, G.; Donaldson, P. M.; Greetham, G. M.; Towrie, M.; Parker, A. W.; Burley, G. A.; Hunt, N. T. Effect of oligomer length on vibrational coupling and energy relaxation in double-stranded DNA. Chem. Phys. 2018, 512, 154– 164,  DOI: 10.1016/j.chemphys.2017.12.010
      28
      Effect of oligomer length on vibrational coupling and energy relaxation in double-stranded DNA
      Hithell, Gordon; Donaldson, Paul M.; Greetham, Gregory M.; Towrie, Michael; Parker, Anthony W.; Burley, Glenn A.; Hunt, Neil T.
      Chemical Physics (2018), 512 (), 154-164CODEN: CMPHC2; ISSN:0301-0104. (Elsevier B.V.)
      The effect of oligomer length on the vibrational mode coupling and energy relaxation mechanisms of AT-rich DNA oligomers in double- and single-stranded conformations has been investigated using two-dimensional IR (2D-IR) spectroscopy. Vibrational coupling of modes of the DNA bases to the sym. stretching vibration of the backbone phosphate group was obsd. for oligomers long enough to form duplex-DNA structures. The coupling was lost upon melting of the duplex. No significant effect of oligomer length or DNA secondary structure was found on either the timescale for vibrational relaxation of the base modes or the mechanism, which was consistent with a cascade process from base modes to intermediate modes, some of which are located on the deoxyribose group, and subsequently to the phosphate backbone. The study shows that vibrational coupling between base and backbone requires formation of the double-helix structure while vibrational energy management is an inherent property of the nucleotide.
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    29. 29
      Zhang, Y.; de La Harpe, K.; Beckstead, A. A.; Martínez-Fernández, L.; Improta, R.; Kohler, B. Excited-State Dynamics of DNA Duplexes with Different H-Bonding Motifs. J. Phys. Chem. Lett. 2016, 7, 950– 954,  DOI: 10.1021/acs.jpclett.6b00074
      29
      Excited-State Dynamics of DNA Duplexes with Different H-Bonding Motifs
      Zhang, Yuyuan; de La Harpe, Kimberly; Beckstead, Ashley A.; Martinez-Fernandez, Lara; Improta, Roberto; Kohler, Bern
      Journal of Physical Chemistry Letters (2016), 7 (6), 950-954CODEN: JPCLCD; ISSN:1948-7185. (American Chemical Society)
      The excited-state dynamics of three distinct forms of the d(GC)9·d(GC)9 DNA duplex were studied by combined time-resolved IR expts. and quantum mech. calcns. In the B- and Z-forms, bases on opposite strands form Watson-Crick (WC) base pairs but stack differently because of salt-induced changes in backbone conformation. At low pH, the two strands assoc. by Hoogsteen (HG) base pairing. UV-induced intrastrand electron transfer (ET) triggers interstrand proton transfer (PT) in the B- and Z-forms, but the PT pathway is blocked in the HG duplex. Despite the different decay mechanisms, a common excited-state lifetime of ∼30 ps is obsd. in all three duplex forms. The ET-PT pathway in the WC duplexes and the solely intrastrand ET pathway in the HG duplex yield the same pair of π-stacked radicals on one strand. Back ET between these radicals is proposed to be the rate-limiting step behind excited-state deactivation in all three duplexes.
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    30. 30
      Schreier, W. J.; Schrader, T. E.; Koller, F. O.; Gilch, P.; Crespo-Hernández, C. E.; Swaminathan, V. N.; Carell, T.; Zinth, W.; Kohler, B. Thymine Dimerization in DNA Is an Ultrafast Photoreaction. Science 2007, 315, 625,  DOI: 10.1126/science.1135428
      30
      Thymine Dimerization in DNA Is an Ultrafast Photoreaction
      Schreier, Wolfgang J.; Schrader, Tobias E.; Koller, Florian O.; Gilch, Peter; Crespo-Hernandez, Carlos E.; Swaminathan, Vijay N.; Carell, Thomas; Zinth, Wolfgang; Kohler, Bern
      Science (Washington, DC, United States) (2007), 315 (5812), 625-629CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Femtosecond time-resolved IR spectroscopy was used to study the formation of cyclobutane dimers in the all-thymine oligodeoxynucleotide (dT)18 by UV light at 272 nm. The appearance of marker bands in the time-resolved spectra indicates that the dimers are fully formed ∼1 ps after UV excitation. The ultrafast appearance of this mutagenic photolesion points to an excited-state reaction that is approx. barrierless for bases that are properly oriented at the instant of light absorption. The low quantum yield of this photoreaction is proposed to result from infrequent conformational states in the unexcited polymer, revealing a strong link between conformation before light absorption and photodamage.
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    31. 31
      Middleton, C. T.; de La Harpe, K.; Su, C.; Law, Y. K.; Crespo-Hernández, C. E.; Kohler, B. DNA Excited-State Dynamics: From Single Bases to the Double Helix. Annu. Rev. Phys. Chem. 2009, 60, 217– 239,  DOI: 10.1146/annurev.physchem.59.032607.093719
      31
      DNA excited-state dynamics: from single bases to the double helix
      Middleton, Chris T.; de La Harpe, Kimberly; Su, Charlene; Law, Yu Kay; Crespo-Hernandez, Carlos E.; Kohler, Bern
      Annual Review of Physical Chemistry (2009), 60 (), 217-239CODEN: ARPLAP; ISSN:0066-426X. (Annual Reviews Inc.)
      A review. UV light is strongly absorbed by DNA, producing excited electronic states that sometimes initiate damaging photochem. reactions. Fully mapping the reactive and nonreactive decay pathways available to excited electronic states in DNA is a decades-old quest. Progress toward this goal has accelerated rapidly in recent years, in large measure because of ultrafast laser expts. Here we review recent discoveries and controversies concerning the nature and dynamics of excited states in DNA model systems in soln. Nonradiative decay by single, solvated nucleotides occurs primarily on the subpicosecond timescale. Surprisingly, excess electronic energy relaxes one or two orders of magnitude more slowly in DNA oligo- and polynucleotides. Highly efficient nonradiative decay pathways guarantee that most excited states do not lead to deleterious reactions but instead relax back to the electronic ground state. Understanding how the spatial organization of the bases controls the relaxation of excess electronic energy in the double helix and in alternative structures is currently one of the most exciting challenges in the field.
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    32. 32
      Torres, J.; Kukol, A.; Goodman, J. M.; Arkin, I. T. Site-specific examination of secondary structure and orientation determination in membrane proteins: The peptidic 13C═18O group as a novel infrared probe. Biopolymers 2001, 59, 396– 401,  DOI: 10.1002/1097-0282(200111)59:6<396::AID-BIP1044>3.0.CO;2-Y
      32
      Site-specific examination of secondary structure and orientation determination in membrane proteins: the peptidic 13C=18O group as a novel infrared probe
      Torres, Jaume; Kukol, Andreas; Goodman, Jonathan M.; Arkin, Isaiah T.
      Biopolymers (2001), 59 (6), 396-401CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
      Detailed site-specific information can be exceptionally useful in structural studies of macromols. in general and proteins in particular. Such information is usually obtained from spectroscopic studies using a label/probe that can reflect on particular properties of the protein. A suitable probe must not modify the native properties of the protein, and should yield interpretable structural information, as is the case with isotopic labels used by Fourier transform IR (FTIR) spectroscopy. In particular, 1-13C=O labels have been shown to relay site-specific secondary structure and orientational information, although limited to small peptides. The reason for this limitation is the high natural abundance of 13C and the lack of baseline resoln. between the main amide I band and the isotope-edited peak. Herein, we dramatically extend the utility of isotope edited FTIR spectroscopy to proteins of virtually any size through the use of a new 1-13C=18O label. The double-isotope label virtually eliminates any contribution from natural abundance 13C. More importantly, the isotope-edited peak is further red-shifted (in accordance with ab initio Hartree-Fock calcns.) and is now completely baseline resolved from the main amide I band. Taken together, this new label enables detn. of site specific secondary structure and orientation in proteins of virtually any size. Even in small peptides 1-13C=18O is far preferable as a label in comparison to 1-13C=16O since it enables anal. without the need for any deconvolution or peak fitting procedures. Finally, the results obtained herein represent the first stage in the application of site-directed dichroism to the structural elucidation of polytopic membrane proteins.
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    33. 33
      Decatur, S. M. Elucidation of Residue-Level Structure and Dynamics of Polypeptides via Isotope-Edited Infrared Spectroscopy. Acc. Chem. Res. 2006, 39, 169– 175,  DOI: 10.1021/ar050135f
      33
      Elucidation of Residue-Level Structure and Dynamics of Polypeptides via Isotope-Edited Infrared Spectroscopy
      Decatur, Sean M.
      Accounts of Chemical Research (2006), 39 (3), 169-175CODEN: ACHRE4; ISSN:0001-4842. (American Chemical Society)
      A review. IR spectroscopy is a powerful tool for analyzing the structure of proteins and peptides. The amide I band is particularly sensitive to the strength and position of the hydrogen bonds that define secondary structure as well as dipole-dipole interactions that are affected by the geometry of the peptide backbone. The introduction of a single 13C-labeled carbonyl into a peptide backbone results in a resolvable shoulder to the main amide I band, which can be analyzed as a sep. peak. Thus, site-specific structural information can be obtained by sequential, systematic labeling of the backbone. This method of isotope-edited IR spectroscopy is a tool for obtaining medium-resoln. information about the backbone conformation and dynamics. This tool has been used to dissect the conformation and dynamics of α helixes and amyloid aggregates, where the versatility of possible sampling with IR spectroscopy is well-suited for studies of large-protein aggregates.
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    34. 34
      Brielle, E. S.; Arkin, I. T. Quantitative Analysis of Multiplex H-Bonds. J. Am. Chem. Soc. 2020, 142, 14150– 14157,  DOI: 10.1021/jacs.0c04357
      34
      Quantitative Analysis of Multiplex H-Bonds
      Brielle, Esther S.; Arkin, Isaiah T.
      Journal of the American Chemical Society (2020), 142 (33), 14150-14157CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      H-bonding is the predominant geometrical determinant of biomol. structure and interactions. As such, considerable analyses have been undertaken to study its detailed energetics. The focus, however, has been mostly reserved for H-bonds comprising a single donor and a single acceptor. Herein, we measure the prevalence and energetics of multiplex H-bonds that are formed between three or more groups. We show that 92% of all transmembrane helixes have at least one non-canonical H-bond formed by a serine or threonine residue whose hydroxyl side chain H-bonds to an over-coordinated carbonyl oxygen at position i-4, i-3, or i in the sequence. Isotope-edited FTIR spectroscopy, coupled with DFT calcns., enables us to det. the bond enthalpies, pointing to values that are up to 127% higher than that of a single canonical H-bond. We propose that these strong H-bonds serve to stabilize serine and threonine residues in hydrophobic environments while concomitantly providing them flexibility between different configurations, which may be necessary for function.
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    35. 35
      Scheerer, D.; Chi, H.; McElheny, D.; Keiderling, T. A.; Hauser, K. Isotopically Site-Selected Dynamics of a Three-Stranded β-Sheet Peptide Detected with Temperature-Jump Infrared-Spectroscopy. J. Phys. Chem. B 2018, 122, 10445– 10454,  DOI: 10.1021/acs.jpcb.8b08336
      35
      Isotopically Site-Selected Dynamics of a Three-Stranded β-Sheet Peptide Detected with Temperature-Jump Infrared-Spectroscopy
      Scheerer, David; Chi, Heng; McElheny, Dan; Keiderling, Timothy A.; Hauser, Karin
      Journal of Physical Chemistry B (2018), 122 (46), 10445-10454CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      IR detected temp.-jump (T-jump) spectroscopy and site-specific isotopic labeling were applied to study a model three-stranded β-sheet peptide with the goal of individually probing the dynamics of strand and turn structural elements. This peptide had two DPro-Gly (pG) turn sequences to stabilize the two component hairpins, which were labeled with 13C=O on each of the Gly residues to resolve them spectroscopically. Labeling the second turn on the amide preceding the DPro (Xxx-DPro amide) provided an alternate turn label as a control. Placing 13C=O labels on specific in-strand residues gave shifted modes that overlap the Xxx-DPro amide I' modes. Their impact could be sepd. from the turn dynamics by a novel difference transient anal. approach. Fourier-transform IR spectra were modeled with d. functional theory-computations which showed the local, isotope-selected vibrations were effectively uncoupled from the other amide I modes. Our T-jump dynamics results, combined with NMR structures and equil. spectral measurements, showed the first turn to be most stable and best formed with the slowest dynamics, whereas the second turn and first strand (N-terminus) had similar dynamics, and the third strand (C-terminus) had the fastest dynamics and was the least structured. The relative dynamics of the strands, Xxx-DPro amides, and 13C-labeled Gly residues on the turns also qual. corresponded to mol. dynamics (MD) simulations of turn and strand fluctuations. MD trajectories indicated the turns to be bistable, with the first turn being Type I' and the second turn flipping from I' to II'. The differences in relaxation times for each turn and the sep. strands revealed that the folding process of this turn-stabilized β-sheet structure proceeds in a multistep process.
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    36. 36
      Setnička, V.; Huang, R.; Thomas, C. L.; Etienne, M. A.; Kubelka, J.; Hammer, R. P.; Keiderling, T. A. IR Study of Cross-Strand Coupling in a β-Hairpin Peptide Using Isotopic Labels. J. Am. Chem. Soc. 2005, 127, 4992– 4993,  DOI: 10.1021/ja043007f
      36
      IR Study of Cross-Strand Coupling in a β-Hairpin Peptide Using Isotopic Labels
      Setnicka, Vladimir; Huang, Rong; Thomas, Catherine L.; Etienne, Marcus A.; Kubelka, Jan; Hammer, Robert P.; Keiderling, Timothy A.
      Journal of the American Chemical Society (2005), 127 (14), 4992-4993CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Model β-hairpin peptides can be used to develop understanding of fundamental elements of β-sheet secondary structure formation and stability. The authors have studied two 13C-labeled variants of a β-hairpin peptide modified from a design originally proposed by S. H. Gellman: Arg-Tyr-Val-Glu-Val-Aib-Gly-Lys-Lys-Ile-Leu-Gln. In this peptide, the Aib-Gly residues form a β-turn, while 13C-labels are on the amide C:O of Val-3, Lys-8 in HBG-L and Val-3, Ile-10 in HBG-S. Both these peptides are labeled on opposite strands of the hairpin, but differ in the labeling pattern. One (HBG-L) forms a large (14-atom) H-bonded ring of labeled C:Os, while the other (HBG-S) forms a small (10-atom) H-bonded ring. These impact the amide I IR spectra, with HBG-L having a 13C frequency and intensity higher than that of HBG-S, in good agreement with the authors' spectral simulations based on quantum mech. derived force fields. The thermal behavior of both peptides yields a broad thermal transition and lacks an isosbestic point. The 13C band for HBG-L has the largest intensity change with temp., distinct from the 12C change and the HBG-S 13C change.
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    37. 37
      Barber-Armstrong, W.; Donaldson, T.; Wijesooriya, H.; Silva, R. A. G. D.; Decatur, S. M. Empirical Relationships between Isotope-Edited IR Spectra and Helix Geometry in Model Peptides. J. Am. Chem. Soc. 2004, 126, 2339– 2345,  DOI: 10.1021/ja037863n
      37
      Empirical Relationships between Isotope-Edited IR Spectra and Helix Geometry in Model Peptides
      Barber-Armstrong, Wendy; Donaldson, Teraya; Wijesooriya, Himali; Silva, R. A. Gangani D.; Decatur, Sean M.
      Journal of the American Chemical Society (2004), 126 (8), 2339-2345CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      IR spectroscopy (IR) is commonly used to study secondary structure of both peptides and proteins. The amide I band is very sensitive to peptide secondary structure, and the conformation of a peptide can be probed at the residue level by introducing site-specific isotope-labels into the peptide backbone. The replacement of a carbonyl 12C with a 13C results in a ∼40 cm-1 shift in the amide I' band. The amide I bands of specifically labeled helixes should vary systematically as a function of the no. and relative spacing of the labeled residues; thus one should be able to describe the conformation of a polypeptide in substantial detail by probing the changes in IR spectra as a function of the no. and positioning of isotope labels. In this study, we report IR spectra of a series of differently labeled helical peptides. A series of 25mer peptides were synthesized based on the repeat sequence (AAAAK)n. We have varied the no. and spacing of the labels on each peptide and studied the changes in the 12C and 13C amide I' band due to label position. Our results indicate that changing the no. of labels changes the frequency and intensity of both the 12C and the 13C amide mode. We also found that varying the spacing between labels causes these amide peaks to shift. Isotope labeling, combined with IR spectroscopy and theor. predictions, may generate a description of peptide backbone conformations at the residue level.
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    38. 38
      Decatur, S. M.; Antonic, J. Isotope-edited infrared spectroscopy of helical peptides. J. Am. Chem. Soc. 1999, 121, 11914– 11915,  DOI: 10.1021/ja991279q
      38
      Isotope-Edited Infrared Spectroscopy of Helical Peptides
      Decatur, Sean M.; Antonic, Jelena
      Journal of the American Chemical Society (1999), 121 (50), 11914-11915CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Short polypeptides which form stable a helixes in aq. soln. are classic models for studying the factors which contribute to helix stability as well as the mechanism of helix formation. The most common tool for characterizing helix content in these peptides is far-UV CD; however, CD spectra can only give information about the overall helix content of a peptide, not the residue-level distribution of helix content within a peptide. Yet, residue-level information is essential to understanding important questions about helix formation and helix stability, such as the characterization and quantification of end-fraying effects and the impact of end-capping interactions. We report that isotope-edited IR spectroscopy opens a new window for observing conformation of specific residues in model helical peptides. IR is a powerful tool for probing the secondary structure of polypeptides in the steady state, and transient IR absorption has been used to observe the kinetics of protein dynamics during folding/unfolding and functional events. The primary spectral feature used in these studies is the amide I' mode. Due to transition dipole coupling between peptide moieties, the amide I' mode is very sensitive to the backbone geometry of a polypeptide, and the frequency and intensity of this band are sensitive to protein secondary structure. However, while a conventional Fourier transform IR (FTIR) spectrum gives information about the overall secondary structure content of the polypeptide, it cannot be used to det. conformations of specific local residues, and thus it is no more useful than CD for studying problems such as end-fraying. One approach to increasing the information content of FTIR spectra is to introduce 13C labels into the peptide backbone. Labeling of backbone carbonyls with 13C results in ∼37 cm-1 shift of the amide I' mode, sepg. the amide I' band of 13C-labeled residues from that of the 12C band. Isotope-edited FTIR has been used to probe the structures of particular regions within a protein and to observe conformational changes involved in protein-protein interactions. We have applied isotope-edited FTIR to probe structural details of an alanine-rich α helical peptide. A series of peptides (L1-L4) were synthesized in which two residues of 1-13C-alanine were incorporated into the sequence.
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    39. 39
      Deng, H.; Vedad, J.; Desamero, R. Z. B.; Callender, R. Difference FTIR Studies of Substrate Distribution in Triosephosphate Isomerase. J. Phys. Chem. B 2017, 121, 10036– 10045,  DOI: 10.1021/acs.jpcb.7b08114
      39
      Difference FTIR Studies of Substrate Distribution in Triosephosphate Isomerase
      Deng, Hua; Vedad, Jayson; Desamero, Ruel Z. B.; Callender, Robert
      Journal of Physical Chemistry B (2017), 121 (43), 10036-10045CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Triosephosphate isomerase (TIM) catalyzes the interconversion between dihydroxyacetone phosphate (DHAP) and D-glyceraldehyde 3-phosphate (GAP), via an enediol(ate) intermediate. The detn. of substrate population distribution in the TIM/substrate reaction mixt. at equil., as well as characterization of the substrate-enzyme interactions in the Michaelis complex are on-going efforts toward the understanding of TIM reaction mechanism. Here, by using isotope-edited difference FITR studies with unlabeled and 13C labeled substrate at specific C atoms, we were able to show that in the reaction mixt. at equil., that the keto substate DHAP was the dominate species and the populations of the aldehyde substrate GAP and intermediate enediol(ate) were very low, consistent with the results from previous X-ray structural and 13C NMR studies. Furthermore, within the DHAP side of the Michaelis complex, there was a set of conformational sub-states that could be characterized by the different C2:O stretch frequencies. The C2:O frequency differences reflected the different degree of the C2:O bond polarization due to H-bonding from active site residues. The C2:O bond polarization has been considered as an important component for the substrate activation within Michaelis complex. We found that in enzyme-substrate reaction mixt. with TIM from different organisms, the no. of sub-states and their population distribution within the DHAP side of the Michaelis complex may be different. These discoveries provide a rare opportunity to probe the interconversion dynamics of these DHAP sub-states, and form the bases in the future studies to det. if the TIM-catalyzed reaction follows a simple linear reaction pathway as previously believed or follows parallel reaction pathways as suggested in another enzyme system that also shows a set of sub-states in the Michaelis complex.
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    40. 40
      Tonge, P. J.; Carey, P. R. Direct observation of the titration of substrate carbonyl groups in the active site of alpha-chymotrypsin by resonance Raman spectroscopy. Biochemistry 1989, 28, 6701,  DOI: 10.1021/bi00442a025
      40
      Direct observation of the titration of substrate carbonyl groups in the active site of α-chymotrypsin by resonance Raman spectroscopy
      Tonge, Peter J.; Carey, Paul R.
      Biochemistry (1989), 28 (16), 6701-9CODEN: BICHAW; ISSN:0006-2960.
      By use of resonance Raman (RR) spectroscopy, the population of the reactive carbonyl group in active acyl-chymotrypsins was characterized and correlated with acyl-enzyme reactivity. RR spectra were obtained, with a flow system and 324- and 337.5-nm excitation, at low and active pH for 6 acyl-chymotrypsins, viz., (indoleacryloyl)-, (4-amino-3-nitrocinnamoyl)-, (furylacryloyl)-, [(5-ethylfuryl)acryloyl]-, (thienylacryloyl)-, and [(5-methylthienyl)acryloyl]-chymotrypsin. These acyl-enzymes represented a 100-fold range of deacylation rate consts. Good RR spectral quality enabled the vibrational spectrum of the carbonyl group at low and active pH in each acyl-enzyme to be obtained. The measured pKa of the spectroscopic changes in the carbonyl region was identical with that for the deacylation kinetics, showing that the RR carbonyl features reflect the ionization state of histidine-57. A carbonyl population was obsd. in the active acyl-enzymes in which the carbonyl O atom of the reactive acyl linkage was H-bonded in the active site. The proportion of this H population, with respect to other obsd. non-H-bonded species, together with the degree of polarization of the carbonyl bond, as monitored by νC:O, was correlated with the deacylation rate consts. of the acyl-enzymes. It was proposed that the H-bonded carbonyl species is located at or near the oxyanion hole and represents the ground state from which deacylation occurs. An increase in the proportion of the H-bonded population and an increase in polarization of the carbonyl bond result in an increase in deacylation rate const. Thus, for the 1st time direct RR data are available on the catalytically transformed region which relate to the difference in acyl-enzyme reactivity.
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    41. 41
      Price, D. A.; Kartje, Z. J.; Hughes, J. A.; Hill, T. D.; Loth, T. M.; Watts, J. K.; Gagnon, K. T.; Moran, S. D. Infrared Spectroscopy Reveals the Preferred Motif Size and Local Disorder in Parallel Stranded DNA G-Quadruplexes. ChemBioChem 2020, 19, 2792– 2804,  DOI: 10.1002/cbic.202000136
      There is no corresponding record for this reference.
    42. 42
      Toyama, A.; Fujimoto, N.; Hanada, N.; Ono, J.; Yoshimitsu, E.; Matsubuchi, A.; Takeuchi, H. Assignments and hydrogen bond sensitivities of UV resonance Raman bands of the C8-deuterated guanine ring. J. Raman Spectrosc. 2002, 33, 699– 708,  DOI: 10.1002/jrs.899
      42
      Assignments and hydrogen bond sensitivities of UV resonance Raman bands of the C8-deuterated guanine ring
      Toyama, Akira; Fujimoto, Naoko; Hanada, Naoki; Ono, Junko; Yoshimitsu, Emiko; Matsubuchi, Akiko; Takeuchi, Hideo
      Journal of Raman Spectroscopy (2002), 33 (9), 699-708CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
      Isotope-edited Raman spectroscopy, a combination of site-selective isotopic labeling and Raman difference spectroscopy, is a useful method for studying the structure and interaction of individual nucleic acid residues in oligonucleotides. To obtain basic data for applying isotope-edited Raman spectroscopy to guanine residues, the authors studied the vibrational modes of UV resonance Raman bands of the C8-deuterated guanine ring by examg. the wavenumber shifts upon seven isotopic substitutions (2-13C, 2-15N, 6-18O, 7-15N, 8-13C, 9-15N and 1'-13C). The H bond sensitivities of the Raman bands were also studied by comparing the Raman spectra recorded in several solvents of different H bonding properties. Some of the Raman bands are markers of H bonding at specific donor or acceptor sites on the guanine ring. The Raman bands, which shift on C8-deuteration, remain in the difference spectrum between the unlabeled and C8-deuterated guanine rings. Among them, a neg. peak around 1525 cm-1 and a strong pos./neg. peak pair around 1485/1465 cm-1 serve as markers of H bonding at N7 and C6=O, resp. Another weak pos./neg. peak pair around 1025/1040 cm-1 is sensitive to H bonding at the proton donor sites (N1 - H and N2 - H2). The applicability of the H bond markers was tested by using a 22-mer oligonucleotide duplex contg. eight guanine residues and its analog in which a single guanine residue is C8-deuterated. The difference spectrum shows that the H bonding state of the guanine residue at the labeled position is consistent with the Watson-Crick base pair structure of DNA. Isotope-edited Raman spectroscopy is a useful tool for studying the H bonding state of selected guanine residues in oligonucleotides.
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    43. 43
      Toyama, A.; Matsubuchi, A.; Fujimoto, N.; Takeuchi, H. Isotope-edited UV Raman spectroscopy of protein–DNA interactions: binding modes of cyclic AMP receptor protein to a natural DNA recognition site. J. Raman Spectrosc. 2005, 36, 300– 306,  DOI: 10.1002/jrs.1289
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      Isotope-edited UV Raman spectroscopy of protein-DNA interactions: binding modes of cyclic AMP receptor protein to a natural DNA recognition site
      Toyama, Akira; Matsubuchi, Akiko; Fujimoto, Naoko; Takeuchi, Hideo
      Journal of Raman Spectroscopy (2005), 36 (4), 300-306CODEN: JRSPAF; ISSN:0377-0486. (John Wiley & Sons Ltd.)
      Isotope-edited UV Raman spectroscopy was applied to the study of the binding mode of cAMP (cAMP) receptor protein (CRP) to a 22-mer oligonucleotide (LacDNA) representing the primary CRP binding site of the E. coli lac promoter. LacDNA contains four guanine residues in the consensus pentamer regions (G5 and G7 on the sense strand and G5' and G7' on the anti-sense strand) and they were individually labeled with deuterium at C(8) on the guanine ring. In the UV (251 nm) Raman difference spectrum between unlabeled and C(8)-D-labeled LacDNA, a sharp pos./neg. peak pair appeared at ,-1490/1465 cm-1, which was assigned to a guanine ring vibration (ν6/ν6') sensitive to the hydrogen bonding state at C(6)=O. CRP is a dimeric protein and forms two complexes with the cofactor cAMP, i.e. half-filled CRP-(cAMP), and fully liganded CRP-(cAMP)2. The ν6/ν6' wavenumbers measured in the presence of CRP showed that CRP-(cAMP)1 binds to G5 and G5' in a sym. manner, whereas CRP-(cAMP)2 exhibits an addnl. binding to G7. Since the base sequence of LacDNA and the structure of CRP-(cAMP)1 are both asym., the sym. LacDNA-CRP-(cAMP)1 interaction suggests that CRP-(cAMP)1, which is considered to be dominant under physiol. conditions, has a conformational flexibility to conform to structural asymmetry of natural DNA sequences. In contrast, the sym. complex CRP-(cAMP)2 binds to LacDNA asym., suggesting a decreased flexibility of CRP in the fully liganded form. Isotope-edited UV Raman spectroscopy provides unique information on the DNA recognition by CRP.
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    44. 44
      Chen, Y.; Eldho, N. V.; Dayie, T. K.; Carey, P. R. Probing Adenine Rings and Backbone Linkages Using Base Specific Isotope-Edited Raman Spectroscopy: Application to Group II Intron Ribozyme Domain V. Biochemistry 2010, 49, 3427– 3435,  DOI: 10.1021/bi902117w
      44
      Probing Adenine Rings and Backbone Linkages Using Base Specific Isotope-Edited Raman Spectroscopy: Application to Group II Intron Ribozyme Domain V
      Chen, Yuanyuan; Eldho, Nadukkudy V.; Dayie, T. Kwaku; Carey, Paul R.
      Biochemistry (2010), 49 (16), 3427-3435CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      Raman difference spectroscopy is used to probe the properties of a 36-nt RNA mol., "D5", which lies at the heart of the catalytic app. in group II introns. For D5 that has all of its adenine residues labeled with 13C and 15N and utilizing Raman difference spectroscopy, we identify the conformationally sensitive -C-O-P-O-C- stretching modes of the unlabeled bonds adjacent to adenine bases, as well as the adenine ring modes themselves. The phosphodiester modes can be assigned to individual adenine residues based on earlier NMR data. The effect of Mg2+ binding was explored by analyzing the Raman difference spectra for [D5 + Mg2+] minus [D5 no Mg2+], for D5 unlabeled, or D5 labeled with 13C/15N-enriched adenine. In both sets of data we assign differential features to G ring modes perturbed by Mg2+ binding at the N7 position. In the A-labeled spectra we attribute a Raman differential near 1450 cm-1 and changes of intensity at 1296 cm-1 to Mg binding at the N7 position of adenine bases. The A and G bases involved in Mg2+ binding again can be identified using earlier NMR results. For the unlabeled D5, a change in the C-O-P-O-C stretch profile at 811 cm-1 upon magnesium binding is due to a "tightening up" (in the sense of a more rigid mol. with less dynamic interchange among competing ribose conformers) of the D5 structure. For adenine-labeled D5, small changes in the adenine backbone bond signatures in the 810-830 cm-1 region suggest that small conformational changes occur in the tetraloop and bulge regions upon binding of Mg2+. The PO2- stretching vibration, near 1100 cm-1, from the nonbridging phosphate groups, probes the effect of Mg2+-hydrate inner-sphere interactions that cause an upshift. In turn, the upshift is modulated by the presence of monovalent cations since in the presence of Na+ and Li+ the upshift is 23 cm-1 while in the presence of K+ and Cs+ it is 13 cm-1, a finding that correlates with the differences in hydration radii. These subtle differences in electrostatic interactions may be related to obsd. variations in catalytic activity. For a reconstructed ribozyme comprising domains 1-3 (D123) connected in cis plus domain 5 (D5) supplied in trans, cleavage of spliced exon substrates in the presence of magnesium and K+ or Cs+ is more efficient than that in the presence of magnesium with Na+ or Li+.
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    45. 45
      Antonopoulos, I. H.; Warner, B. A.; Carey, P. R. Concerted Protein and Nucleic Acid Conformational Changes Observed Prior to Nucleotide Incorporation in a Bacterial RNA Polymerase: Raman Crystallographic Evidence. Biochemistry 2015, 54, 5297– 5305,  DOI: 10.1021/acs.biochem.5b00484
      45
      Concerted Protein and Nucleic Acid Conformational Changes Observed Prior to Nucleotide Incorporation in a Bacterial RNA Polymerase: Raman Crystallographic Evidence
      Antonopoulos, Ioanna H.; Warner, Brittany A.; Carey, Paul R.
      Biochemistry (2015), 54 (34), 5297-5305CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      Transcription elongation requires the continuous incorporation of ribonucleotide triphosphates into a growing transcript. RNA polymerases (RNAPs) are able to processively synthesize a growing RNA chain via translocation of the RNAP enzyme along its nucleic acid template strand after each nucleotide addn. cycle. In this work, a time-resolved Raman spectroscopic anal. of nucleotide addn. in single crystals of the Thermus thermophilus elongation complex (TthEC) is reported. When [13C,15N]GTP (*GTP) is soaked into crystals of the TthEC, large reversible changes in the Raman spectrum that are assigned to protein and nucleic acid conformational events during a single-nucleotide incorporation are obsd. The *GTP population in the TthEC crystal reaches a stable population at 37 min, while substantial and reversible protein conformational changes (mainly ascribed to changes in α-helical Raman features) maximize at approx. 50 min. At the same time, changes in nucleic acid bases and phosphodiester backbone Raman marker bands occur. Catalysis begins at approx. 65-70 min, soon after the maximal protein and DNA changes, and is monitored via the decline in a triphosphate vibrational Raman mode from *GTP. The Raman data indicate that approx. 40% of the total triphosphate population, present as *GTP, reacts in the crystal. This may suggest that a second population of noncovalently bound *GTP resides in a site distinct from the catalytic site. The data reported here are an extension of our recent work on the elongation complex (EC) of a bacterial RNAP, Thermus thermophilus (Tth), where Raman spectroscopy and polyacrylamide gel electrophoresis were employed to monitor incorporation and misincorporation in single TthEC crystals. Therefore, the initial study establishes the groundwork for this study. In contrast to our previous study, in which incorporation takes place very rapidly inside the crystals, the data on this single crystal exhibit a slower time regime, which allows the dissection of the structural dynamics assocd. with GMP incorporation within the TthEC crystal.
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    46. 46
      Antonopoulos, I. H.; Murayama, Y.; Warner, B. A.; Sekine, S.-i.; Yokoyama, S.; Carey, P. R. Time-Resolved Raman and Polyacrylamide Gel Electrophoresis Observations of Nucleotide Incorporation and Misincorporation in RNA within a Bacterial RNA Polymerase Crystal. Biochemistry 2015, 54, 652– 665,  DOI: 10.1021/bi501166r
      46
      Time-Resolved Raman and Polyacrylamide Gel Electrophoresis Observations of Nucleotide Incorporation and Misincorporation in RNA within a Bacterial RNA Polymerase Crystal
      Antonopoulos, Ioanna H.; Murayama, Yuko; Warner, Brittany A.; Sekine, Shun-ichi; Yokoyama, Shigeyuki; Carey, Paul R.
      Biochemistry (2015), 54 (3), 652-665CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      The bacterial RNA polymerase (RNAP) elongation complex (EC) is highly stable and is able to extend an RNA chain for thousands of nucleotides. Understanding the processive mechanism of nucleotide addn. requires detailed structural and temporal data for the EC reaction. Here, a time-resolved Raman spectroscopic anal. is combined with PAGE to monitor nucleotide addn. in single crystals of the Thermus thermophilus EC (TthEC) RNAP. When the cognate base GTP, labeled with 13C and 15N (*GTP), is soaked into crystals of the TthEC, changes in the Raman spectra show evidence of nucleotide incorporation and product formation. The major change is the redn. of *GTP's triphosphate intensity. Nucleotide incorporation is confirmed by PAGE assays. Both Raman and PAGE methods have a time resoln. of minutes. There is also Raman spectroscopic evidence of a second population of *GTP in the crystal that does not become covalently linked to the nascent RNA chain. When this population is removed by "soaking out" (placing the crystal in a soln. that contains no NTP), there are no perturbations to the Raman difference spectra, indicating that conformational changes are not detected in the EC. In contrast, the misincorporation of the noncognate base, 13C- and 15N-labeled UTP (*UTP), gives rise to large spectroscopic changes. As in the GTP expt., redn. of the triphosphate relative intensity in the Raman soak-in data shows that the incorporation reaction occurs during the first few minutes of our instrumental dead time. This is also confirmed by PAGE anal. Whereas PAGE data show *GTP converts 100% of the nascent RNA 14mer to 15mer, the noncognate *UTP converts only ∼50%. During *UTP soak-in, there is a slow, reversible formation of an α-helical amide I band in the Raman difference spectra peaking at 40 min. Similar to *GTP soak-in, *UTP soak-in shows Raman spectroscopic evidence of a second noncovalently bound *UTP population in the crystal. Moreover, the second population has a marked effect on the complex's conformational states because removing it by "soaking-out" unreacted *UTP causes large changes in protein and nucleic acid Raman marker bands in the time range of 10-100 min. The conformational changes obsd. for noncognate *UTP may indicate that the enzyme is prepg. for proofreading to excise the misincorporated base. This idea is supported by the PAGE results for *UTP soak-out that show endonuclease activity is occurring.
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    47. 47
      Hoogsteen, K. The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine. Acta Crystallogr. 1963, 16, 907– 916,  DOI: 10.1107/S0365110X63002437
      47
      The crystal and molecular structure of a hydrogen-bonded complex between 1-methylthymine and 9-methyladenine
      Hoogsteen, Karst
      Acta Crystallographica (1963), 16 (9), 907-16CODEN: ACCRA9; ISSN:0365-110X.
      Crystals of a 1:1 H-bonded complex between 1-methylthymine and 9-methyladenine can be grown from an aq. soln. contg. equimol. quantities of the 2 compds. The crystals are monoclinic, with a 8.304, b 6.552, c 12.837 A. and β = 106° 50'. The space group is P21/m, with 2 base-pair complexes in the unit cell. The structure was refined with 3-dimensional data taken with Cu-radiation. The positional coordinates and anisotropic temp. factors of the heavy atoms were obtained by least-sqs. analyses. The H atoms, except those of 2 Me groups, were located from a 3-dimensional difference Fourier synthesis. The 1-methylthymine and 9-methyladenine mols. form a planar base pair lying in a mirror plane and are connected to one another by 2 nearly linear H bonds, from the NH2 group of 9-methyladenine to O(9) of 1-methylthymine (2.846 A.) and N(3) of 1-methylthymine to N(7) of 9-methyladenine (2.924 A.). This structure differs from the adenine-thymine pairing proposed by Watson and Crick [Nature 171, 737 (1953)], where N3 of thymine is H-bonded to N1 of adenine. The distance between the Me group at N1 of 1-methylthymine and the one at N9 of 9-methyladenine is 8.645 A., whereas this distance is 11.1 A. in the pairing proposed by W. and C. (CA 48, 5113d).
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    48. 48
      Zhang, S. L.; Michaelian, K. H.; Loppnow, G. R. Vibrational Spectra and Experimental Assignments of Thymine and Nine of Its Isotopomers. J. Phys. Chem. A 1998, 102, 461– 470,  DOI: 10.1021/jp972385m
      48
      Vibrational Spectra and Experimental Assignments of Thymine and Nine of Its Isotopomers
      Zhang, Shuliang L.; Michaelian, Kirk H.; Loppnow, Glen R.
      Journal of Physical Chemistry A (1998), 102 (2), 461-470CODEN: JPCAFH; ISSN:1089-5639. (American Chemical Society)
      FT-IR and FT-Raman spectra of polycryst. natural abundance thymine, nine of its isotopic derivs., and 2-thiothymine (5-methyl-2-thiouracil) are reported from 50 to 3500 cm-1. The isotopic derivs. are thymine-6-13C, thymine-α-13C, thymine-15N2, thymine-α,α,α,6-d4, and their resp. N-deuterated compds. The vibrational spectra are assigned using the frequency shifts upon isotopic substitution and are compared to previous assignments, both exptl. and ab initio based. Extensive mixing of the vibrations in the region below 1750 cm-1 complicates the vibrational assignments in this region. However, many of the exocyclic stretching and bending vibrations are assigned with confidence, and many of the couplings can be ascertained with these thymine derivs. The spectra of the isotopic derivs. described here resolve many of the controversial assignments in the literature and correct some previously misassigned vibrational bands. This represents the most complete exptl. vibrational study of thymine to date and provides a useful exptl. basis for future theor. calcns.
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    49. 49
      Peng, C. S.; Jones, K. C.; Tokmakoff, A. Anharmonic Vibrational Modes of Nucleic Acid Bases Revealed by 2D IR Spectroscopy. J. Am. Chem. Soc. 2011, 133, 15650– 15660,  DOI: 10.1021/ja205636h
      49
      Anharmonic Vibrational Modes of Nucleic Acid Bases Revealed by 2D IR Spectroscopy
      Peng, Chunte Sam; Jones, Kevin C.; Tokmakoff, Andrei
      Journal of the American Chemical Society (2011), 133 (39), 15650-15660CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Polarization-dependent two-dimensional IR (2D IR) spectra of the purine and pyrimidine base vibrations of five nucleotide monophosphates (NMPs) were acquired in D2O at neutral pH in the frequency range 1500-1700 cm-1. The distinctive cross-peaks between the ring deformations and carbonyl stretches of NMPs indicate that these vibrational modes are highly coupled, in contrast with the traditional peak assignment, which is based on a simple local mode picture such as C=O, C=N, and C=C double bond stretches. A model of multiple anharmonically coupled oscillators was employed to characterize the transition energies, vibrational anharmonicities and couplings, and transition dipole strengths and orientations. No simple or intuitive structural correlations are found to readily assign the spectral features, except in the case of guanine and cytosine, which contain a single local CO stretching mode. To help interpret the nature of these vibrational modes, we performed d. functional theory (DFT) calcns. and found that multiple ring vibrations are coupled and delocalized over the purine and pyrimidine rings. Generally, there is close correspondence between the exptl. and computational results, provided that the DFT calcns. include explicit waters solvating hydrogen-bonding sites. These results provide direct exptl. evidence of the delocalized nature of the nucleotide base vibrations via a nonperturbative fashion and will serve as building blocks for constructing a structure-based model of DNA and RNA vibrational spectroscopy.
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    50. 50
      Leonard, G. A.; McAuleyhecht, K.; Brown, T.; Hunter, W. N. Do C-H...O Hydrogen-Bonds Contribute To The Stability Of Nucleic-Acid Base-Pairs. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1995, 51, 136– 139,  DOI: 10.1107/S0907444994004713
      50
      Do C-H...O hydrogen bonds contribute to the stability of nucleic acid base pairs?
      Leonard G A; McAuley-Hecht K; Brown T; Hunter W N
      Acta crystallographica. Section D, Biological crystallography (1995), 51 (Pt 2), 136-9 ISSN:0907-4449.
      The possible formation of inter-base C-H.O hydrogen bonds in A.T, A.U and certain non-Watson-Crick base pairs is examined. A geometrical analysis in conjunction with implications for the thermodynamic stability of the base pairs suggests that C-H.O hydrogen bonds could form in nucleic acid base pairs. They may alleviate destabilizing interactions that would arise if an unsatisfied hydrogen-bond acceptor were present and mediate secondary hydrogen-bonding effects in these base pairs.
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    51. 51
      Ghosh, A.; Bansal, M. C–H···O hydrogen bonds in minor groove of A-tracts in DNA double helices. J. Mol. Biol. 1999, 294, 1149– 1158,  DOI: 10.1006/jmbi.1999.3323
      51
      C-H..O Hydrogen Bonds in Minor Groove of A-tracts in DNA Double Helices
      Ghosh, Anirban; Bansal, Manju
      Journal of Molecular Biology (1999), 294 (5), 1149-1158CODEN: JMOBAK; ISSN:0022-2836. (Academic Press)
      Anal. of available B-DNA type oligomeric crystal structures as well as protein-bound DNA fragments (solved using data with resoln. <2.6 Å) indicates that in both data sets, a majority of the (3'-Ade) H2..O2(3'-Thy/Cyt) distances in AA.TT and GA.TC dinucleotide steps, are considerably shorter than their values in a uniform fiber model, and are smaller than their optimum sepn. distance. Since the electropos. C2-H2 group of adenine is in close proximity of the electroneg. keto oxygen atoms of both pyrimidine bases in the antiparallel strand of the double-helical DNA structures, it suggests the possibility of intra-base-pair as well as cross-strand C-H..O hydrogen bonds in the minor groove. The C2-H2..O2 hydrogen bonds within the A.T base-pairs could be a natural consequence of Watson-Crick pairing. However, the close cross-strand interactions between the bases at the 3'-ends of the AA.TT and GA.TC steps arise due to the local sequence-dependent geometry of these steps. While the base-pair propeller twist in these steps is comparable to the fiber model, some of the other local parameters such as base-pair opening angle and inter-base-pair slide show coordinated changes, leading to these shorter C2-H2..O2 distances. Hence, in addn. to the well-known minor groove hydration, it appears that favorable C2-H2..O2 cross-strand interactions may play a role in imparting a characteristic geometry to AA.TT and GA.TC steps, as well as An.Tn and GAn.TnC tracts, which leads to a narrow minor groove in these regions. (c) 1999 Academic Press.
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    52. 52
      Srinivasadesikan, V.; Sahu, P. K.; Lee, S.-L. Spectroscopic probe on N–H···N, N–H···O and controversial C–H···O contact in A–T base pair: A DFT study. Spectrochim. Acta, Part A 2014, 120, 542– 547,  DOI: 10.1016/j.saa.2013.11.110
      52
      Spectroscopic probe on N-H···N, N-H···O and controversial C-H···O contact in A-T base pair: A DFT study
      Srinivasadesikan, Venkatesan; Sahu, Prabhat K.; Lee, Shyi-Long
      Spectrochimica Acta, Part A: Molecular and Biomolecular Spectroscopy (2014), 120 (), 542-547CODEN: SAMCAS; ISSN:1386-1425. (Elsevier B.V.)
      DNA base pair A-T was studied by IR and NMR spectroscopy using DFT methods. The results were analyzed in terms of IR vibrational frequencies and 1H NMR chem. shifts. Different types of interactions N-H···N, N-H···O and C-H···O types were studied in DNA base pairs. Although, previous reports argued about the 3rd C-H···O type interaction in A-T base pair, such typical interaction was analyzed thoroughly by IR and NMR spectroscopy using DFT methods. The CH···O interaction in the A-T base pair is a weak interaction compared to normal hydrogen bond interactions.
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    53. 53
      Šponer, J.; Leszczynski, J.; Hobza, P. Structures and Energies of Hydrogen-Bonded DNA Base Pairs. A Nonempirical Study with Inclusion of Electron Correlation. J. Phys. Chem. A 1996, 100, 1965– 1974,  DOI: 10.1021/jp952760f
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      Structures and Energies of Hydrogen-Bonded DNA Base Pairs. A Nonempirical Study with Inclusion of Electron Correlation
      Sponer, Jiri; Leszczynski, Jerzy; Hobza, Pavel
      Journal of Physical Chemistry (1996), 100 (5), 1965-74CODEN: JPCHAX; ISSN:0022-3654. (American Chemical Society)
      Hydrogen bonding of DNA bases was investigated by reliable nonempirical ab initio calcns. Gradient optimization was carried out on 30 DNA base pairs using the Hartree-Fock (HF) approxn. and the 6-31G** basis set of AOs. The optimizations were performed within Cs symmetry. However, the harmonic vibrational anal. indicates that 13 of the studied base pairs are intrinsically nonplanar. Interaction energies of base pairs were then evaluated at the planar optimized geometries with inclusion of the electron correlation energy using the second-order Moeller-Plesset (MP2) method. The stabilization energies of the studied base pairs range from -24 to -9 kcal/mol, and the calcd. gas phase interaction enthalpies agree well (within 2 kcal/mol) with the available exptl. values. The binding energies and mol. structures of the base pairs are not detd. solely by the hydrogen bonds, but they are also strongly influenced by the polarity of the monomers and by a wide variety of secondary long-range electrostatic interactions that also involve the hydrogen atoms bonded to ring carbon atoms. The stabilization of the base pairs is dominated by the Hartree-Fock interaction energy. This result confirms that the stability of the base pairs originates in the electrostatic interactions. For weakly bonded base pairs, the correlation interaction energy amts. to as much as 30-40% of the stabilization. For some other base pairs, however, repulsive correlation interaction energy was found. The latter fact is explained as a result of a redn. of the electrostatic attraction upon inclusion of the electron correlation. The empirical London dispersion energy does not reproduce the correlation interaction energy. For the sake of comparison, results of a first gradient optimization for a DNA base pair at a correlated level (CC base pair, MP2/6-31G** level) are reported. In addn., the ability of the economical d. functional theory (DFT) method to reproduce the ab initio data was investigated. The DFT method with present functionals is not suitable to consistently study the whole range of the DNA base interactions. However, it gives good ests. of interaction energies at the ref. HF/6-31G** geometries.
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    54. 54
      Shishkin, O. V.; Sponer, J.; Hobza, P. Intramolecular flexibility of DNA bases in adenine-thymine and guanine-cytosine Watson-Crick base pairs. J. Mol. Struct. 1999, 477, 15– 21,  DOI: 10.1016/S0022-2860(98)00603-6
      54
      Intramolecular flexibility of DNA bases in adenine-thymine and guanine-cytosine Watson-Crick base pairs
      Shishkin, Oleg V.; Sponer, Jiri; Hobza, Pavel
      Journal of Molecular Structure (1999), 477 (1-3), 15-21CODEN: JMOSB4; ISSN:0022-2860. (Elsevier Science B.V.)
      The conformational flexibility of pyrimidine rings in adenine (A)-thymine (T) and guanine (G)-cytosine (C) Watson-Crick base pairs was investigated at the ab initio Hartree-Fock (HF) level using 6-31G** basis set. Transition of these rings from the planar equil. conformation to a distorted sofa conformation with torsion angles of 20° results in a marginal energy increase of approx. 1.3 kcal/mol for the A-T pair and 3.5 kcal/mol for the G-C pair. In the GC pair, the simultaneous deformation of both pyrimidine rings was applied. Comparison of ring deformation energies calcd. at the HF, with correlated levels indicates significant overestimation (up to 30%) of ring rigidity by the HF approxn. Reasonable correlations were found between the out-of-plane ring vibrational frequencies and the ring deformation energies. Formation of Watson-Crick base pairs is manifested in prolongation of the N-H bonds within the bases which results in significant redn. of the N-H stretching frequencies. On the basis of the calcd. increase in the C-H stretching frequency of adenine, the existence of a third hydrogen bond of the C-H···O type in the A-T pair is ruled out.
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    55. 55
      Shui, X.; Sines, C. C.; McFail-Isom, L.; VanDerveer, D.; Williams, L. D. Structure of the Potassium Form of CGCGAATTCGCG: DNA Deformation by Electrostatic Collapse around Inorganic Cations. Biochemistry 1998, 37, 16877– 16887,  DOI: 10.1021/bi982063o
      55
      Structure of the Potassium Form of CGCGAATTCGCG: DNA Deformation by Electrostatic Collapse around Inorganic Cations
      Shui, Xiuqi; Sines, Chad C.; McFail-Isom, Lori; VanDerveer, Don; Williams, Loren Dean
      Biochemistry (1998), 37 (48), 16877-16887CODEN: BICHAW; ISSN:0006-2960. (American Chemical Society)
      The potassium form of d(CGCGAATTCGCG) solved by x-ray diffraction to 1.75 Å resoln. indicates that monovalent cations penetrate the primary and secondary layers of the "spine of hydration". Both the sodium [Shui, X., McFail-Isom, L., Hu, G. G., and Williams, L. D. (1998) Biochem. 37, 8341-8355] and the potassium forms of the dodecamer at high resoln. indicate that the original description of the spine, only two layers deep and with full occupancy by water mols., requires substantive revision. The spine is merely the bottom two layers of a four layer solvent structure. The four layers combine to form a repeating motif of fused hexagons. The top two solvent layers were not apparent from previous medium-resoln. diffraction data. We propose that the narrow minor groove and axial curvature of A-tract DNA arise from localization of cations within the minor groove. In general, the results described here support a model in which most or all forces that drive DNA away from canonical B-conformation are extrinsic and arise from interaction of DNA with its environment. Intrinsic forces, originating from direct base-base interactions such as stacking, hydrogen bonding, and steric repulsion among exocyclic groups appear to be insignificant. The time-averaged positions of the ubiquitous inorg. cations that surround DNA are influenced by DNA bases. The distribution of cations depends on sequence. Regions of high and low cation d. are generated spontaneously in the solvent region by heterogeneous sequence or even within the grooves of homopolymers. The regions of high and low cation d. deform DNA by electrostatic collapse. Thus, the effects of small inorg. cations on DNA structure are similar to the effects of proteins.
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    56. 56
      Woods, K. K.; Lan, T.; McLaughlin, L. W.; Williams, L. D. The role of minor groove functional groups in DNA hydration. Nucleic Acids Res. 2003, 31, 1536– 1540,  DOI: 10.1093/nar/gkg240
      56
      The role of minor groove functional groups in DNA hydration
      Woods, Kristen Kruger; Lan, Tao; McLaughlin, Larry W.; Williams, Loren Dean
      Nucleic Acids Research (2003), 31 (5), 1536-1540CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
      Here we describe the crystal structure of modified [d(CGCGAATTCGCG)]2 refined to 2.04 Å. The modification, which affects only the two thymines at the central ApT step, involves isosteric removal of the 2-keto oxygen atoms and substitution of the N1 nitrogen with carbon. The crystal structure reveals the ability of this modified thymine to effectively base pair with adenine in [d(CGCGAAtTCGCG)]2. The structure also suggests that the minor groove "spine of hydration" is destabilized but essentially intact.
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    57. 57
      Schneider, B.; Berman, H. M. Hydration of the DNA bases is local. Biophys. J. 1995, 69, 2661– 2669,  DOI: 10.1016/S0006-3495(95)80136-0
      57
      Hydration of the DNA bases is local
      Schneider, Bohdan; Berman, Helen M.
      Biophysical Journal (1995), 69 (6), 2661-9CODEN: BIOJAU; ISSN:0006-3495. (Biophysical Society)
      Ordered hydration sites were detd. for the nucleotide bases in B-type conformations using the crystal structure data on 14 B-DNA decamer structures. A method of d. representation was extended so that positions, occupancies, and distributions of the hydration sites were predicted around a B-DNA double helix by a method analogous to crystallog. refinement. The predicted hydration sites correctly reproduce the main features of hydration around the B-DNA dodecamer. In contrast, to the previous observations, the newly available crystal data show the same extent of hydration of guanine and adenine, and of cytosine and thymine.
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    58. 58
      Shakked, Z.; Guzikevich-Guerstein, G.; Frolow, F.; Rabinovich, D.; Joachimiak, A.; Sigler, P. B. Determinants of repressor/operator recognition from the structure of the trp operator binding site. Nature 1994, 368, 469– 473,  DOI: 10.1038/368469a0
      58
      Determinants of repressor/operator recognition from the structure of the trp operator binding site
      Shakked, Z.; Guzikevich-Guerstein, G.; Frolow, F.; Rabinovich, D.; Joachimiak, A.; Sigler, P. B.
      Nature (London, United Kingdom) (1994), 368 (6470), 469-73CODEN: NATUAS; ISSN:0028-0836.
      On the basis of the crystal structure of the trp repressor/operator complex, it has been proposed that the specificity of the interaction can be explained not only by direct hydrogen bonding and non-polar contacts between the protein and the bases of its target DNA, but also by indirect structural effects and water-mediated interactions. To understand the contribution of DNA structure and hydration in this context, the structure of the free DNA must be compared with its structure when complexed with the protein. Here the authors present the high-resoln. crystal structure of the trp operator region that is most important in the recognition process. By comparing the free and bound states of the DNA regulatory sequence, the authors show that the structure and hydration of the DNA target are important elements in its recognition by the repressor protein.
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    59. 59
      Drew, H. R.; Wing, R. M.; Takano, T.; Broka, C.; Tanaka, S.; Itakura, K.; Dickerson, R. E. Structure of a B-DNA dodecamer: conformation and dynamics. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 2179,  DOI: 10.1073/pnas.78.4.2179
      59
      Structure of a B-DNA dodecamer. I. Conformation and dynamics
      Drew, Horace R.; Wing, Richard M.; Takano, Tsunehiro; Broka, Christopher; Tanaka, Shoji; Itakura, Keiichi; Dickerson, Richard E.
      Proceedings of the National Academy of Sciences of the United States of America (1981), 78 (4), 2179-83CODEN: PNASA6; ISSN:0027-8424.
      The crystal structure of the synthetic DNA dodecamer d(CpGpCpGpApApTpTpCpGpCpG) was refined to a residual error of R = 17.8% at 1.9-Å resoln. (2-σ data). The mol. forms slightly >1 complete turn of right-handed double-stranded B helix. The 2 ends of the helix overlap and interlock minor grooves with neighboring mols. up and down a 21 screw axis, producing a 19° bend in helix axis over the 11-base-pair steps of the dodecamer. In the center of the mol., where perturbation is least, the helix has a mean rotation of 36.9° per step, or 9.8 base pairs per turn. The mean propeller twist (total dihedral angle between base planes) between A·T base pairs in the center of the mol. is 17.3°, and that between C·G pairs on the 2 ends avs. 11.5°. Individual deoxyribose ring conformations, measured by the C5'-C4'-C3'-O3' torsion angle δ, exhibit an approx. Gaussian distribution centered around the C1'-exo position with δav. = 123° and a range of 79-157°. Purine sugars cluster at high δ values, and pyrimidine sugars cluster at lower δ. A tendency toward 2-fold symmetry in sugar conformation about the center of the mol. is detectable in spite of the destruction of ideal 2-fold symmetry by the mol. bending. More strikingly, sugar conformations of paired bases appear to follow a principle of anticorrelation, with δ values lying approx. the same distance to either side of the center value, δ = 123°. This same anticorrelation is also obsd. in other DNA and DNA·RNA structures.
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    60. 60
      Valls, N.; Wright, G.; Steiner, R. A.; Murshudov, G. N.; Subirana, J. A. DNA variability in five crystal structures of d (CGCAATTGCG). Spectrochim. Acta, Part A 2004, 60, 680– 685,  DOI: 10.1107/S0907444904002896
      There is no corresponding record for this reference.
    61. 61
      Edwards, K. J.; Brown, D. G.; Spink, N.; Skelly, J. V.; Neidle, S. Molecular structure of the B-DNA dodecamer d(CGCAAATTTGCG)2 An examination of propeller twist and minor-groove water structure at 2·2Åresolution. J. Mol. Biol. 1992, 226, 1161– 1173,  DOI: 10.1016/0022-2836(92)91059-X
      61
      Molecular structure of the B-DNA dodecamer d(CGCAAATTTGCG)2. An examination of propeller twist and minor-groove water structure at 2.2Å resolution
      Edwards, Karen J.; Brown, David G.; Spink, Neil; Skelly, Jane V.; Neidle, Stephen
      Journal of Molecular Biology (1992), 226 (4), 1161-73CODEN: JMOBAK; ISSN:0022-2836.
      The crystal structure of the dodecanucleotide duplex d(CGCAAATTTGCG)2 has been solved to 2.2Å resoln. and refined to an R-factor of 18.1% with the inclusion of 71 water mols. The structure shows propeller twists of up to -20° for the A·T base-pairs, although there is probably only one (weak) three-center hydrogen bond in the six base-pair AT narrow minor-groove region. An extensive ribbon of hydration has been located in this groove that has features distinctive from the classic spine of hydration. Solvation around phosphate groups is described, with several instances of water mols. bridging between phosphates.
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    62. 62
      Larsen, T. A.; Kopka, M. L.; Dickerson, R. E. Crystal structure analysis of the B-DNA dodecamer CGTGAATTCACG. Biochemistry 1991, 30, 4443– 9,  DOI: 10.1021/bi00232a010
      62
      Crystal structure analysis of the B-DNA dodecamer CGTGAATTCACG
      Larsen, Teresa A.; Kopka, Mary L.; Dickerson, Richard E.
      Biochemistry (1991), 30 (18), 4443-9CODEN: BICHAW; ISSN:0006-2960.
      The crystal structure of the DNA dodecamer C-G-T-G-A-A-T-T-C-A-C-G has been detd. at a resoln. of 2.5 Å, with a final R factor of 15.8% for 1475 nonzero reflections measured at 0 °. The structure is isomorphous with that of the Drew dodecamer, with that space group P212121 and cell dimensions of a = 24.94 Å, b = 40.78 Å, and c = 66.13 Å. The asym. unit contains all 12 base pairs of the B-DNA double helix and 36 water mols. The structure of C-G-T-G-A-A-T-T-C-A-C-G is very similar to that of Drew dodecamer C-G-C-G-A-A-T-T-C-G-C-G, with no major alterations in helix parameters. A hierarchy of credibility of the local helix parameters at intermediate resoln. is proposed. In order of descending accuracy, these are (a) backbone pathway and minor-groove width, (b) base-pair long-axis parameters, such as twist and tilt, (c) base-pair short-axis parameters such as propeller, buckle, cup, and rise, and (d) sugar-ring conformation and main-chain torsion angles. Water peaks in the refined structure appear to represent a selection of peaks that were obsd. in the Drew dodecamer. The minor-grrove spine of hydration at 2.5 Å is fragmentary, but as N. Narendra et al. (1991) have obsd., lowering the temp. leads to a more complete representation of the spine.
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    63. 63
      Vlieghe, D.; Turkenburg, J. P.; Van Meervelt, L. B-DNA at atomic resolution reveals extended hydration patterns. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1999, 55, 1495– 502,  DOI: 10.1107/S0907444999007933
      63
      B-DNA at atomic resolution reveals extended hydration patterns
      Vlieghe, Dominique; Turkenburg, Johan P.; Van Meervelt, Luc
      Acta Crystallographica, Section D: Biological Crystallography (1999), D55 (9), 1495-1502CODEN: ABCRE6; ISSN:0907-4449. (Munksgaard International Publishers Ltd.)
      Despite the importance of hydration around DNA in the understanding of its conformation and interactions with other mols. in many biol. processes, only limited at. resoln. information is available. Crystal-engineering techniques, which were originally developed to mimic DNA base triplets in a crystal lattice, also eliminate the rotational disorder of oligonucleotides around their helical axis and thereby enhance the resoln. of the structure anal. The low-temp. crystal structure of the synthetic DNA decamer d(GGCCAATTGG) has been detd. at at. resoln. (1.15 A) using 17700 reflections and the highly organized hydration patterns in both grooves have been characterized. The narrow d(AATT) minor groove is occupied by an "extended hydration spine" alternately bridging base pairs and phosphate O1P atoms of opposite strands, while a distinctive pattern of parallel water ribbons is obsd. in the major groove. This anal. provides structural insight into the correlation found between narrow minor-groove width and occurrence of the BI conformation and can be used to design new minor-groove binders. By their location between adjacent helixes, two fully hydrated magnesium ions further stabilize the crystal packing. The structure also provides details of the hydration and conformation of G·GC triple helixes.
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    64. 64
      Liepinsh, E.; Otting, G.; Wüthrich, K. NMR observation of individual molecules of hydration water bound to DNA duplexes: direct evidence for a spine of hydration water present in aqueous solution. Nucleic Acids Res. 1992, 20, 6549– 6553,  DOI: 10.1093/nar/20.24.6549
      64
      NMR observation of individual molecules of hydration water bound to DNA duplexes: direct evidence for a spine of hydration water present in aqueous solution
      Liepinsh, Edvards; Otting, Gottfried; Wuethrich, Kurt
      Nucleic Acids Research (1992), 20 (24), 6549-53CODEN: NARHAD; ISSN:0305-1048.
      The residence times of individual hydration water mols. in the major and minor grooves of DNA were measured by NMR spectroscopy in aq. solns. of d(CGCGAATTCGCG)2 and d(AAAAATTTTT)2. The exptl. observations were nuclear Overhauser effects (NOE) between water protons and the protons of the DNA. The pos. sign of NOEs with the thymine Me groups shows that the residence times of the hydration water mols. near these protons in the major groove of the DNA must be shorter than about 500 ps, which coincides with the behavior of surface hydration water in peptides and proteins. Neg. NOEs were obsd. with the hydrogen atoms in position 2 of adenine in both duplexes studied. This indicates that a spine of hydration in the minor groove, as obsd. by x-ray diffraction in DNA crystals, is present also in soln., with residence times significantly longer than 1 ns. Such residence times are reminiscent of interior hydration water mols. in globular proteins, which are an integral part of the mol. architecture both in soln. and in crystals.
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    65. 65
      Halle, B.; Denisov, V. P. Water and monovalent ions in the minor groove of B-DNA oligonucleotides as seen by NMR. Biopolymers 1998, 48, 210– 233,  DOI: 10.1002/(SICI)1097-0282(1998)48:4<210::AID-BIP3>3.0.CO;2-Y
      65
      Water and monovalent ions in the minor groove of B-DNA oligonucleotides as seen by NMR
      Halle B; Denisov V P
      Biopolymers (1998), 48 (4), 210-33 ISSN:0006-3525.
      During the past 8 years, two complementary nmr techniques-magnetic relaxation dispersion and nuclear Overhauser effect spectroscopy-have been applied extensively to the study of water and monovalent ions in the minor groove of B-DNA oligonucleotides in solution. In this review, the possibilities and limitations of the two methods are outlined, with emphasis on the interpretational steps whereby molecular-level information is extracted from the primary data. The results on sequence-dependent hydration and ion-DNA interactions obtained so far by these methods is summarized and critically assessed. The nmr results are also compared with structural data from x-ray crystallography.
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    66. 66
      Fingerhut, B. P.; Elsaesser, T. Noncovalent Interactions of Hydrated DNA and RNA Mapped by 2D-IR Spectroscopy. In Springer Series in Optical Sciences, Cho, M., Ed.; Springer Singapore: Singapore, 2019; Vol. 226, pp 171– 195.
      There is no corresponding record for this reference.
    67. 67
      Guchhait, B.; Liu, Y.; Siebert, T.; Elsaesser, T. Ultrafast vibrational dynamics of the DNA backbone at different hydration levels mapped by two-dimensional infrared spectroscopy. Struct. Dyn. 2015, 3, 043202  DOI: 10.1063/1.4936567
      There is no corresponding record for this reference.
    68. 68
      Siebert, T.; Guchhait, B.; Liu, Y.; Costard, R.; Elsaesser, T. Anharmonic Backbone Vibrations in Ultrafast Processes at the DNA–Water Interface. J. Phys. Chem. B 2015, 119, 9670– 9677,  DOI: 10.1021/acs.jpcb.5b04499
      68
      Anharmonic backbone vibrations in ultrafast processes at the DNA-water interface
      Siebert, Torsten; Guchhait, Biswajit; Liu, Yingliang; Costard, Rene; Elsaesser, Thomas
      Journal of Physical Chemistry B (2015), 119 (30), 9670-9677CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      The vibrational modes of the deoxyribose-phosphodiester backbone moiety of DNA and their interactions with the interfacial aq. environment were addressed with 2-dimensional (2D) IR spectroscopy on a femtosecond-to-picosecond time scale. Beyond the current understanding in the harmonic approxn., the anharmonic character and delocalization of the backbone modes in the frequency range of 900-1300 cm-1 were detd. with both diagonal anharmonicities and intermode couplings on the order of 10 cm-1. Mediated by the intermode couplings, energy transfer between the backbone modes took place on a picosecond time scale, parallel to vibrational relaxation and energy dissipation into the environment. Probing structural dynamics noninvasively via the time evolution of the 2D lineshapes, limited structural fluctuations were obsd. on a 300-fs time scale of low-frequency motions of the helix, counterions, and water shell. Structural disorder of the DNA-water interface and DNA-water H-bonds were, however, preserved for times beyond 10 ps. The different interactions of limited strength ensure ultrafast vibrational relaxation and dissipation of excess energy in the backbone structure, processes that are important for the structural integrity of hydrated DNA.
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    69. 69
      Yang, M.; Szyc, Ł.; Elsaesser, T. Decelerated Water Dynamics and Vibrational Couplings of Hydrated DNA Mapped by Two-Dimensional Infrared Spectroscopy. J. Phys. Chem. B 2011, 115, 13093– 13100,  DOI: 10.1021/jp208166w
      69
      Decelerated Water Dynamics and Vibrational Couplings of Hydrated DNA Mapped by Two-Dimensional Infrared Spectroscopy
      Yang, Ming; Szyc, Lukasz; Elsaesser, Thomas
      Journal of Physical Chemistry B (2011), 115 (44), 13093-13100CODEN: JPCBFK; ISSN:1520-5207. (American Chemical Society)
      Double-stranded DNA oligomers contg. 23 alternating adenine-thymine base pairs are studied at different hydration levels by femtosecond 2-dimensional (2D) IR spectroscopy. Coupled NH stretching modes of the A-T pairs and OH stretching excitations of the H2O shell are discerned in the 2-dimensional spectra. Limited changes of NH stretching frequencies and line shapes with increasing hydration suggest spectral dynamics governed by DNA rather than H2O fluctuations. But OH stretching excitations of the H2O shell around fully hydrated DNA undergo spectral diffusion on a ∼ 500 fs time scale. The center line slopes of the 2-dimensional spectra of hydrated DNA demonstrate a slower decay of the frequency-time correlation function (TCF) than that in neat H2O, as is evident from a comparison with 2-dimensional spectra of neat H2O and theor. TCFs. The authors attribute this behavior to reduced structural fluctuations of the H2O shell and a reduced rate of resonant OH stretching energy transfer.
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    70. 70
      Feig, M.; Pettitt, B. M. Modeling high-resolution hydration patterns in correlation with DNA sequence and conformation11Edited by B. Honig. J. Mol. Biol. 1999, 286, 1075– 1095,  DOI: 10.1006/jmbi.1998.2486
      70
      Modeling High-resolution Hydration Patterns in Correlation with DNA Sequence and Conformation
      Feig, Michael; Pettitt, B. Montgomery
      Journal of Molecular Biology (1999), 286 (4), 1075-1095CODEN: JMOBAK; ISSN:0022-2836. (Academic Press)
      Hydration around the DNA fragment d(C5T5)·(A5G5) is presented from two mol. dynamics simulations of 10 and 12 ns total simulation time. The DNA has been simulated as a flexible mol. with both the CHARMM and AMBER force fields in explicit solvent including counterions and 0.8 M addnl. NaCl salt. From the previous anal. of the DNA structure B-DNA conformations were found with the AMBER force-field and A-DNA conformations with CHARMM parameters. High-resoln. hydration patterns are compared between the two conformations and between C·G and T·A base-pairs from the homopolymeric parts of the simulated sequence. Crystallog. results from a statistical anal. of hydration sites around DNA crystal structures compare very well with the simulation results. Differences between the crystal sites and our data are explained by variations in conformation, sequence, and limitations in the resoln. of water sites by crystal diffraction. Hydration layers are defined from radial distribution functions and compared with exptl. results. Excellent agreement is found when the measured exptl. quantities are compared with the equiv. distribution of water mols. in the first hydration shell. The no. of water mols. bound to DNA was found smaller around T·A base-pairs and around A-DNA as compared to B-DNA. This is partially offset by a larger no. of water mols. in hydrophobic contact with DNA around T·A base-pairs and around A-DNA. The nos. of water mols. in minor and major grooves have been correlated with helical roll, twist, and inclination angles. The data more fully explain the obsd. B A transition at low humidity. (c) 1999 Academic Press.
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    71. 71
      Young, M. A.; Jayaram, B.; Beveridge, D. L. Intrusion of Counterions into the Spine of Hydration in the Minor Groove of B-DNA: Fractional Occupancy of Electronegative Pockets. J. Am. Chem. Soc. 1997, 119, 59– 69,  DOI: 10.1021/ja960459m
      71
      Intrusion of Counterions into the Spine of Hydration in the Minor Groove of B-DNA: Fractional Occupancy of Electronegative Pockets
      Young, Matthew A.; Jayaram, B.; Beveridge, D. L.
      Journal of the American Chemical Society (1997), 119 (1), 59-69CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      A sequence of ordered solvent peaks in the electron d. map of the minor groove region of ApT-rich tracts of the double helix is a characteristic of B-form DNA well established from crystallog. This feature, termed the "spine of hydration", has been discussed as a stabilizing feature of B-DNA, the structure of which is known to be sensitive to environmental effects. Nanosecond-range mol. dynamics simulations on the DNA duplex of sequence d(CGCGAATTCGCG) have been carried out, including explicit consideration of ∼4000 water mols. and 22 Na+ counterions, and based on the new AMBER 4.1 force field with the particle mesh Ewald summation used in the treatment of long-range interactions. The calcns. support a dynamical model of B-DNA closer to the B form than any previously reported. Anal. of the dynamical structure of the solvent revealed that, in over half of the trajectory, a Na+ ion is found in the minor groove localized at the ApT step. This position, termed herein the "ApT pocket", was noted previously (Lavery, R.; Pullman, B. J. Biomol. Struct. Dyn. 1985, 5, 1021) to be of uniquely low neg. electrostatic potential relative to other positions of the groove, a result supported by the location of a Na+ ion in the crystal structure of the dApU miniduplex [Seeman, N.; et al. J. Mol. Biol. 1976, 104, 109] and by addnl. calcns. described herein based on continuum electrostatics. The Na+ ion in the ApT pocket interacts favorably with the thymine O2 atom on opposite strands of the duplex and is well articulated with the water mols. which constitute the remainder of the minor groove spine. This result indicates that counterions may intrude on the minor groove spine of hydration on B-form DNA and subsequently influence the environmental structure and thermodn. in a sequence-dependent manner. The obsd. narrowing of the minor groove in the AATT region of the d(CGCGAATTCGCG) structure may be due to direct binding effects and also to indirect modulation of the electrostatic repulsions that occur when a counterion resides in the minor groove "AT pocket". The idea of localized complexation of otherwise mobile counterions in electroneg. pockets in the grooves of DNA helixes introduces a heretofore mostly unappreciated source of sequence-dependent effects on local conformational, helicoidal, and morphol. structure and may have important implications in understanding the functional energetics and specificity of the interactions of DNA and RNA with regulatory proteins, pharmaceutical agents, and other ligands.
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    72. 72
      Stelling, A. L.; Xu, Y.; Zhou, H.; Choi, S. H.; Clay, M. C.; Merriman, D. K.; Al-Hashimi, H. M. Robust IR-based detection of stable and fractionally populated G-C+ and A-T Hoogsteen base pairs in duplex DNA. FEBS Lett. 2017, 591, 1770– 1784,  DOI: 10.1002/1873-3468.12681
      72
      Robust IR-based detection of stable and fractionally populated G-C+ and A-T Hoogsteen base pairs in duplex DNA
      Stelling, Allison L.; Xu, Yu; Zhou, Huiqing; Choi, Seung H.; Clay, Mary C.; Merriman, Dawn K.; Al-Hashimi, Hashim M.
      FEBS Letters (2017), 591 (12), 1770-1784CODEN: FEBLAL; ISSN:0014-5793. (Wiley-Blackwell)
      Noncanonical G-C+ and A-T Hoogsteen base pairs can form in duplex DNA and play roles in recognition, damage repair, and replication. Identifying Hoogsteen base pairs in DNA duplexes remains challenging due to difficulties in resolving syn vs. antipurine bases with x-ray crystallog.; and size limitations and line broadening can make them difficult to characterize by NMR spectroscopy. Here, it was shown that IR spectroscopy can identify G-C+ and A-T Hoogsteen base pairs in duplex DNA across a range of different structural contexts. The utility of IR-based detection of Hoogsteen base pairs is demonstrated by characterizing the first example of adjacent A-T and G-C+ Hoogsteen base pairs in a DNA duplex where severe broadening complicates detection with NMR.
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    73. 73
      Damha, M. J.; Ogilvie, K. K. Oligoribonucleotide Synthesis. In Protocols for Oligonucleotides and Analogs; Springer, 1993; Vol. 20, pp 81– 114.
      There is no corresponding record for this reference.
    74. 74
      Xu, Y.; McSally, J.; Andricioaei, I.; Al-Hashimi, H. M. Modulation of Hoogsteen dynamics on DNA recognition. Nat. Commun. 2018, 9, 1473  DOI: 10.1038/s41467-018-03516-1
      74
      Modulation of Hoogsteen dynamics on DNA recognition
      Xu Yu; Al-Hashimi Hashim M; Xu Yu; Al-Hashimi Hashim M; McSally James; Andricioaei Ioan
      Nature communications (2018), 9 (1), 1473 ISSN:.
      In naked duplex DNA, G-C and A-T Watson-Crick base pairs exist in dynamic equilibrium with their Hoogsteen counterparts. Here, we used nuclear magnetic resonance (NMR) relaxation dispersion and molecular dynamics (MD) simulations to examine how Watson-Crick/Hoogsteen dynamics are modulated upon recognition of duplex DNA by the bisintercalator echinomycin and monointercalator actinomycin D. In both cases, DNA recognition results in the quenching of Hoogsteen dynamics at base pairs involved in intermolecular base-specific hydrogen bonds. In the case of echinomycin, the Hoogsteen population increased 10-fold for base pairs flanking the chromophore most likely due to intermolecular stacking interactions, whereas actinomycin D minimally affected Hoogsteen dynamics at other sites. Modulation of Hoogsteen dynamics at binding interfaces may be a general phenomenon with important implications for DNA-ligand and DNA-protein recognition.
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    75. 75
      Gilbert, D. E.; Feigon, J. Proton NMR study of the [d(ACGTATACGT)]2-2echinomycin complex: conformational changes between echinomycin binding sites. Nucleic Acids Res. 1992, 20, 2411– 2420,  DOI: 10.1093/nar/20.10.2411
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      Proton NMR study of the [d(ACGTATACGT)]2-2echinomycin complex: conformational changes between echinomycin binding sites
      Gilbert, Dara E.; Feigon, Juli
      Nucleic Acids Research (1992), 20 (10), 2411-20CODEN: NARHAD; ISSN:0305-1048.
      The interactions of echinomycin and the DNA decamer [d(ACGTATACGT)]2 were studied by proton NMR. Echinomycin binds cooperatively as a bisintercalator at the CpG steps. The terminal A-T base pairs are Hoogsteen base paired, but none of the four central A-T base pairs are Hoogsteen base paired. However, binding of the drug induces unwinding of the DNA which is propagated to the central ApT step. All four central A-T base pairs are destabilized relative to those in the free DNA. Furthermore, based on these and other results, the authors conclude that the formation of stable Hoogsteen base pairs may not be the relevant structural change in vivo. The structural changes propagated between adjacent ACGT binding sites are the unwinding of the duplex and destabilization of the base pairing between binding sites.
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    76. 76
      Gilbert, D. E.; Feigon, J. The DNA sequence at echinomycin binding sites determines the structural changes induced by drug binding: NMR studies of echinomycin binding to [d (ACGTACGT)] 2 and [d (TCGATCGA)] 2. Biochemistry 1991, 30, 2483– 2494,  DOI: 10.1021/bi00223a027
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      The DNA sequence at echinomycin binding sites determines the structural changes induced by drug binding: NMR studies of echinomycin binding to [d(ACGTACGT)]2 and [d(TCGATCGA)]2
      Gilbert, Dara E.; Feigon, Juli
      Biochemistry (1991), 30 (9), 2483-94CODEN: BICHAW; ISSN:0006-2960.
      The complexes formed between the cyclic octadepsipeptide antibiotic echinomycin and the two DNA octamers [d(ACGTACGT)]2 and [d(TCGATCGA)]2 were investigated by using one- and two-dimensional proton NMR spectroscopy techniques. The results obtained for the two complexes are compared with each other, with the crystal structures of related DNA-echinomycin complexes, and with enzymic and chem. footprinting results. In the satd. complexes, two echinomycin mols. bind to each octamer by bisintercalation of the quinoxaline moieties on either side of each CpG step. Binding of echinomycin to the octamer [d(ACGTACGT)]2 is cooperative so that only the two-drug complex is obsd. at lower drug-DNA ratios, but binding to [d(TCGATCGA)]2 is not cooperative. At low temps., both the internal and terminal A·T base pairs adjacent to the binding site in the [d(ACGTACGT)]2-2 echinomycin complex are Hoogsteen base paired as obsd. in related crystal structures. However, as the temp. is raised, the internal A·T Hoogsteen base pairs are destabilized and are obsd. to be exchanging between the Hoogsteen base-paired and an open (or Watson-Crick base-paired) state. In contrast, in the [d(TCGATCGA)]2-2 echinomycin complex, no A·T Hoogsteen base pairs are obsd., the internal A·T base pairs appear to be stabilized by drug binding, and the structure of the complex does not change significantly from 0 to 45°. Thus, the structure and stability of the DNA in echinomycin-DNA complexes depends on the sequence at and adjacent to the binding site. While no single structural change in the DNA can explain all of the footprinting results, unwinding of the DNA helix in the drug-DNA complexes appears to be an important factor while Hoogsteen base pair formation does not.
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    77. 77
      Gao, X.; Patel, D. J. Antitumour drug-DNA interactions: NMR studies of echinomycin and chromomycin complexes. Q. Rev. Biophys. 1989, 22, 93– 138,  DOI: 10.1017/S0033583500003814
      77
      Antitumor drug-DNA interactions: NMR studies of echinomycin and chromomycin complexes
      Gao, Xiaolian; Patel, Dinshaw J.
      Quarterly Reviews of Biophysics (1989), 22 (2), 93-138CODEN: QURBAW; ISSN:0033-5835.
      A review with 54 refs.
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    78. 78
      Gilbert, D. E.; van der Marel, G. A.; van Boom, J. H.; Feigon, J. Unstable Hoogsteen base pairs adjacent to echinomycin binding sites within a DNA duplex. Proc. Natl. Acad. Sci. U.S.A. 1989, 86, 3006– 3010,  DOI: 10.1073/pnas.86.9.3006
      78
      Unstable Hoogsteen base pairs adjacent to echinomycin binding sites within a DNA duplex
      Gilbert, Dara E.; Van der Marel, Gijs A.; Van Boom, Jacques H.; Feigon, Juli
      Proceedings of the National Academy of Sciences of the United States of America (1989), 86 (9), 3006-10CODEN: PNASA6; ISSN:0027-8424.
      The bis-intercalation complex present between the DNA octamer [d(ACGTACGT)]2 and the cyclic octadepsipeptide antibiotic echinomycin (I) has been studied by one- and two-dimensional proton NMR, and the results obtained have been compared with the crystal structures of related DNA-echinomycin complexes. Two echinomycins bind cooperatively to each DNA duplex at the CpG steps, with the two quinoxaline rings of each echinomycin bis-intercalating between the C·G and A·T base pairs. At low temps., the A·T base pairs on either side of the intercalation site adopt the Hoogsteen conformation, as obsd. in the crystal structures. As the temp. is raised, the Hoogsteen base pairs in the interior of the duplex are destabilized and are obsd. to be exchanging between the Hoogsteen base pair and either an open or a Watson-Crick base-paired state. The terminal A·T base pairs, which are not as constrained by the helix as the internal base pairs, remain stably Hoogsteen base-paired up to at least 45°. The implications of these results for the biol. role of Hoogsteen base pairs in echinomycin-DNA complexes in vivo are discussed.
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    79. 79
      Gao, X.; Patel, D. J. NMR studies of echinomycin bisintercalation complexes with d (A1-C2-G3-T4) and d (T1-C2-G3-A4) duplexes in aqueous solution: sequence-dependent formation of Hoogsteen A1-T4 and Watson-Crick T1-A4 base pairs flanking the bisintercalation site. Biochemistry 1988, 27,