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ARTICLESDynamics

A New Algorithm for Efficient Direct Dynamics Calculations of Large-Curvature Tunneling and Its Application to Radical Reactions with 9−15 Atoms
Antonio Fernández-Ramos - and
Donald G. Truhlar
We present a new algorithm for carrying out large-curvature tunneling calculations that account for extreme corner-cutting tunneling in hydrogen atom, proton, and hydride transfer reactions. The algorithm is based on two-dimensional interpolation in a physically motived set of variables that span the space of tunneling paths and tunneling energies. With this new algorithm, we are able to carry out density functional theory direct dynamics calculations of the rate constants, including multidimensional tunneling, for a set of hydrogen atom transfer reactions involving 9−15 atoms and up to 7 nonhydrogenic atoms. The reactions considered involve the abstraction of a hydrogen atom from hydrocarbons by a trifluoromethyl radical, and in particular, we consider the reactions of CF3 with CH4, C2H6, and C3H8. We also calculate several kinetic isotope effects. The electronic structure is treated by the MPWB1K/6-31+G(d,p) method, which is validated by comparison to experimental results and to CBS-Q, MCG3, and G3SX(MP3) calculations for CF3 + CH4. Harmonic vibrational frequencies along the reaction path are calculated in curvilinear coordinates with scaled frequencies, and anharmonicity is included in the lowest-frequency torsion.
Quantum Chemistry

Does a Sodium Atom Bind to C60?
Jose Pitarch-Ruiz - ,
Stefano Evangelisti - , and
Daniel Maynau
A Multi-Reference Configuration-Interaction study of the NaC60 system is presented. It is shown that the experimentally measured dipole moment of this system can be explained by the existence of a charge-transfer state of Na+C60- nature. Moreover, the present work shows that Configuration-Interaction techniques based on local orbitals permit a Multi-Reference treatment of systems containing several tens of atoms.

Chemical Notions from the Electron Density
Jaime Fernández Rico - ,
Rafael López - ,
Ignacio Ema - , and
Guillermo Ramírez
The study of density and the role played by its atomic representation is proposed as a way for the rationalization of chemical behavior. As this behavior has been long rationalized in terms of the basic concepts of empirical structural chemistry, a direct link between both approaches is searched for by using the exact representation of the density provided by the deformed atoms in molecules method (Rico, J. F.; López, R.; Ema, I.; Ramírez, G.; Ludeña, E. J. Comput. Chem. 2004, 25, 1355−1363). Noting that the spherical terms of the pseudoatoms cannot be mainly responsible for the chemical behavior, we study the small nonspherical deformations and find that they reflect and support all basic concepts of empirical structural chemistry. Lone pairs; single, double, and triple bonds; different classes of atoms; functional groups; and so forth are paralleled by the density deformations in a neat manner. These facts are illustrated with several examples.

Interacting Quantum Atoms: A Correlated Energy Decomposition Scheme Based on the Quantum Theory of Atoms in Molecules
M. A. Blanco - ,
A. Martín Pendás - , and
E. Francisco
We make use of the Quantum Theory of Atoms in Molecules (QTAM) to partition the total energy of a many-electron system into intra- and interatomic terms, by explicitly computing both the one- and two-electron contributions. While the general scheme is formally equivalent to that by Bader et al., we focus on the separation and computation of the atomic self-energies and all the interaction terms. The partition is ultimately performed within the density matrices, in analogy with McWeeny's Theory of Electronic Separability, and then carried onto the energy. It is intimately linked with the atomistic picture of the chemical bond, not only allowing the separation of different two-body contributions (point-charge-like, multipolar, total Coulomb, exchange, correlation, ...) to the interaction between a pair of atoms but also including an effective many-body contribution to the binding (self-energy, formally one-body) due to the deformation of the atoms within the many-electron system as compared to the free atoms. Many qualitative ideas about the chemical bond can be quantified using this scheme.

A Theoretical Investigation of the Geometries and Binding Energies of Molecular Tweezer and Clip Host−Guest Systems
Maja Parac - ,
Mihajlo Etinski - ,
Miljenko Peric - , and
Stefan Grimme
A quantum chemical study of host−guest systems with dimethylene-bridged clips and tetramethylene-bridged tweezers as host molecules and six different aliphatic and aromatic substrates as guests is presented. The geometries and binding energies of the complexes are investigated using the recently developed density functional theory with empirical corrections for dispersion interactions (DFT-D) in combination with the BLYP functional and basis sets of TZVP quality. It is found that the DFT-D method provides accurate geometries for the host−guest complexes that compare very favorably to experimental X-ray data. Without the dispersion correction, all host−guest complexes are unbound at the pure DFT level. Calculations of the clip complexes show that the DFT-D binding energies of the guests agree well with those from a more sophisticated SCS-MP2/aug-cc-pVTZ treatment. By a partitioning of the host into molecular fragments it is shown that the binding energy is clearly dominated by the aromatic units of the clip. An energy decomposition analysis of the interaction energies of some tweezer complexes revealed the decisive role of the electrostatic and dispersion contributions for relative stabilities. The calculations on the tweezer complexes show that the benzene spaced tweezer is a better receptor for aliphatic substrates than its naphthalene analogue that has a better topology for the binding of aromatic substrates. The tweezer with a OAc substituent in the central spacer unit is found to favor complex formation with both aliphatic and aromatic substrates. The theoretical results are qualitatively in very good agreement with previous experimental findings although direct comparison with experimental binding energies which include solvent effects is not possible. The good results obtained with the DFT-D-BLYP method suggest this approach as a standard tool in supramolecular chemistry and as the method of choice for theoretical structure determinations of large complexes where both electrostatic and dispersive interactions are crucial.

Considerations for Reliable Calculation of 77Se Chemical Shifts
Craig A. Bayse
The theoretical chemical shifts of a large series of selenium compounds have been calculated using GIAO-MP2 and -DFT methods in several basis sets. Reliable chemical shifts are calculated for many compounds, especially with the mPW1PW91 exchange-correlation functional and either a triple-ζ basis set (tzvp: 13% mean absolute error) or a limited RECP set chosen for practical applications on complex molecules (BSL: 11.8% mean absolute error). Molecules with three-center-four-electron bonding or low-lying n→π* states require additional diffuse functions and nonperturbative methods, respectively, but terminal selenium anions cannot be calculated reliably in the gas phase due to the neglect of solvation. When these cases are excluded, the mean absolute error decreases from 16.5% to 8.9% in GIAO-MP2/BSL but only slightly for DFT methods.

Distributed Multipole Analysis: Stability for Large Basis Sets
Anthony J. Stone
The distributed multipole analysis procedure, for describing a molecular charge distribution in terms of multipole moments on the individual atoms (or other sites) of the molecule, is not stable with respect to a change of basis set, and indeed, the calculated moments change substantially and unpredictably when the basis set is improved, even though the resulting electrostatic potential changes very little. A revised procedure is proposed, which uses grid-based quadrature for partitioning the contributions to the charge density from diffuse basis functions. The resulting procedure is very stable, and the calculated multipole moments converge rapidly to stable values as the size of the basis is increased.
SM6: A Density Functional Theory Continuum Solvation Model for Calculating Aqueous Solvation Free Energies of Neutrals, Ions, and Solute−Water Clusters
Casey P. Kelly - ,
Christopher J. Cramer - , and
Donald G. Truhlar
A new charge model, called Charge Model 4 (CM4), and a new continuum solvent model, called Solvation Model 6 (SM6), are presented. Using a database of aqueous solvation free energies for 273 neutrals, 112 ions, and 31 ion−water clusters, parameter sets for the mPW0 hybrid density functional of Adamo and Barone (Adamo, C.; Barone, V. J. Chem. Phys. 1998, 108, 664−675) were optimized for use with the following four basis sets: MIDI!6D, 6-31G(d), 6-31+G(d), and 6-31+G(d,p). SM6 separates the observable aqueous solvation free energy into two different components: one arising from long-range bulk electrostatic effects and a second from short-range interactions between the solute and solvent molecules in the first solvation shell. This partition of the observable solvation free energy allows SM6 to effectively model a wide range of solutes. For the 273 neutral solutes in the test set, SM6 achieves an average error of ∼0.50 kcal/mol in the aqueous solvation free energies. For solutes, especially ions, that have highly concentrated regions of charge density, adding an explicit water molecule to the calculation significantly improves the performance of SM6 for predicting solvation free energies. The performance of SM6 was tested against several other continuum models, including SM5.43R and several different implementations of the Polarizable Continuum Model (PCM). For both neutral and ionic solutes, SM6 outperforms all of the models against which it was tested. Also, SM6 is the only model (except for one with an average error 3.4 times larger) that improves when an explicit solvent molecule is added to solutes with concentrated charge densities. Thus, in SM6, unlike the other continuum models tested here, adding one or more explicit solvent molecules to the calculation is an effective strategy for improving the prediction of the aqueous solvation free energies of solutes with strong local solute−solvent interactions. This is important, because local solute−solvent interactions are not specifically accounted for by bulk electrostatics, but modeling these interactions correctly is important for predicting the aqueous solvation free energies of certain solutes. Finally, SM6 retains its accuracy when used in conjunction with the B3LYP and B3PW91 functionals, and in fact the solvation parameters obtained with a given basis set may be used with any good density functional or fraction of Hartree−Fock exchange.

Electron-Impact Ionization Cross Sections of Molecules Containing Heavy Elements (Z > 10)
Gregory E. Scott - and
Karl K. Irikura
The binary-encounter-Bethe (BEB) theory has been successful for computing electron-impact ionization cross sections of many molecules. For molecules that contain heavy atoms (defined here as atoms with valence principal quantum number n > 2), there are two alternative BEB procedures in the literature. The first involves a kinetic-energy correction for molecular orbitals that are dominated by atomic orbitals with n > 2. The second alternative is to use effective core potentials (ECPs), which were developed for other purposes but yield valence pseudo-orbitals with reduced kinetic energies. In the present study, the results of these two approaches are compared with experimental cross sections for several molecules containing heavy elements. Although both procedures perform well, the ECP results agree somewhat better with experimental measurements. Cross sections are presented for C2Cl6, C2HCl5, C2Cl4, both isomers of C2H2Cl4, CCl4, TiCl4, CBr4, CHBr3, CH2Br2, P2, P4, As2, As4, GaCl, CS2, H2S, CH3I, Al(CH3)3, Ga(CH3)3, hexamethyldisiloxane, and Zn(C2H5)2. Incorrect BEB calculations have been reported in the literature for several of these molecules. As an ancillary result, the dipole polarizability of Zn(C2H5)2 is predicted to be 12.1 Å3.

Ab Initio Study of Spin-Vibronic Dynamics in the Ground X̃2E and Excited Ã2A1 Electronic States of CH3S•
Aleksandr V. Marenich - and
James E. Boggs
A spin-vibronic Hamiltonian including the linear, quadratic, cubic, and quartic Jahn−Teller terms with account for all important anharmonic effects was applied to study electronic and nuclear dynamics in the ground X̃2E and first excited Ã2A1 electronic states of the CH3S methylthio radical (C3v). The E⊗(3a1+3e) problem of spin-vibronic eigenvalues and eigenfunctions was solved in a basis set of products of electronic, electron spin, and vibrational functions. The Jahn−Teller distortions in X̃2E CH3S are totally quenched by the strong spin−orbit coupling. However, Jahn−Teller interaction terms in the spin-vibronic Hamiltonian cannot be neglected for the high precision evaluation of energy levels of CH3S. The results of calculations show the importance of inclusion of at least quadratic vibronic terms into variational treatment. The nonadiabatic (pseudo-Jahn−Teller) coupling of the X̃2E and Ã2A1 electronic states was found small and safely removable from the spin-vibronic Hamiltonian of CH3S.

Metal−Polyhydride Molecules Are Compact Inside a Fullerene Cage
Laura Gagliardi
Quantum chemical calculations show that metal−hydride molecules are more compact when they are placed inside a fullerene cage than when they are isolated molecules. The metal−hydrogen bond distance in ZrH4 becomes 0.15 Å shorter when it is placed inside a C60 cage. Metal−polyhydride molecules with a large number of H atoms such as ScH15 and ZrH16, which are not bound as isolated molecules, are predicted to be bound inside a fullerene cage. It is also shown that two TiH16 clusters are bound inside a bicapped (9,0) carbon nanotube. Possible ways to make metal−hydrides inside C60 and nanotubes are suggested.

An Efficient Real Space Multigrid QM/MM Electrostatic Coupling
Teodoro Laino - ,
Fawzi Mohamed - ,
Alessandro Laio - , and
Michele Parrinello
A popular strategy for simulating large systems where quantum chemical effects are important is the use of mixed quantum mechanical/molecular mechanics methods (QM/MM). While the cost of solving the Schrödinger equation in the QM part is the bottleneck of these calculations, evaluating the Coulomb interaction between the QM and the MM part is surprisingly expensive. In fact it can be just as time-consuming as solving the QM part. We present here a novel real space multigrid approach that handles Coulomb interactions very effectively and implement it in the CP2K code. This novel scheme cuts the cost of this part of the calculation by 2 orders of magnitude. The method does not need very fine-tuning or adjustable parameters, and it is quite accurate, leading to a dynamics with very good energy conservation. We exemplify the validity of our algorithms with simulations of water and of a zwitterionic dipeptide solvated in water.

1-Fluoropropane. Torsional Potential Surface
Lionel Goodman - and
Ronald R. Sauers
The systematic deletion of orbital interactions, using natural bond orbital (NBO) theory at the B3LYP/ 6-311++G(3df,2p) level, provides validation for the anti-C−H/C−F* hyperconjugative interaction providing the backbone for the gauche preference of 1-fluoropropane (FP). The FCCC torsional coordinate taking trans FP to gauche FP is predicted to be strongly contaminated by CCC bending with the result that a large part of the trans → gauche stabilization energy stems from mode coupling. The anti-C−H/C−F* hyperconjugative interaction is also found to play a major, if not determining, role in the coupling. The results of Rydberg deletion calculations suggest that Rydberg interactions play a role in NBO analysis, contrary to the usual assumption that interactions involving Rydberg orbitals can be ignored.
Slater's Exchange Parameters α for Analytic and Variational Xα Calculations
Rajendra R. Zope - and
Brett I. Dunlap
Recently, we formulated a fully analytical and variational implementation of a subset of density functional theory using Gaussian basis sets to express orbital and the one-body effective potential. The implementation, called the Slater-Roothaan (SR) method, is an extension of Slater's Xα method, which allows arbitrary scaling of the exchange potential around each type of atom in a heteroatomic system. The scaling parameter is Slater's exchange parameter, α, which can be determined for each type of atom by choosing various criteria depending on the nature of problem undertaken. Here, we determine these scaling parameters for atoms H through Cl by constraining some physical quantity obtained from the self-consistent solution of the SR method to be equal to its exact value. Thus, the sets of α values that reproduce the exact atomic energies have been determined for four different combinations of basis sets. A similar set of α values that is independent of a basis set is obtained from numerical calculations. These sets of α parameters are subsequently used in the SR method to compute atomization energies of the G2 set of molecules. The mean absolute error in atomization energies is about 17 kcal/mol and is smaller than that of the Hartree−Fock theory (78 kcal/mol) and the local density approximation (40 kcal/mol) but larger than that of a typical generalized gradient approximation (∼8 kcal/mol). A second set of α values is determined by matching the highest occupied eigenvalue of the SR method to the negative of the first ionization potential. Finally, the possibility of obtaining α values from the exact atomization energy of homonuclear diatomic molecules is explored. We find that the molecular α values show much larger deviation than what is observed for the atomic α values. The α values obtained for atoms in combination with an analytic SR method allow elemental properties to be extrapolated to heterogeneous molecules. In general, the sets of different α values might be useful for calculations of different properties using the analytic and variational SR method.
Spectroscopy and Excited States

Effects of Peripheral Substituents on the Electronic Structure and Properties of Unligated and Ligated Metal Phthalocyanines, Metal = Fe, Co, Zn
Meng-Sheng Liao - ,
John D. Watts - ,
Ming-Ju Huang - ,
Sergiu M. Gorun - ,
Tapas Kar - , and
Steve Scheiner
The effects of peripheral, multiple −F as well as −C2F5 substituents, on the electronic structure and properties of unligated and ligated metal phthalocyanines, PcM, PcM(acetone)2 (M = Fe, Co, Zn), PcZn(Cl), and PcZn(Cl-), have been investigated using a DFT method. The calculations provide a clear explanation for the changes in the ground state, molecular orbital (MO) energy levels, ionization potentials (IP), electron affinities (EA), charge distribution on the metal (QM), axial binding energies, and in electronic spectra. While the strongly electron-withdrawing −C2F5 groups on the Pc ring change the ground state of PcFe, they do not influence the ground state of PcCo. The IP is increased by ∼1.3 eV from H16PcM to F16PcM and by another ∼1.1 eV from F16PcM to F48PcM. A similar increase in the EA is also found on going from H16PcM to F48PcM. Substitution by the −C2F5 groups also considerably increases the binding strength between PcM and the electron-donating axial ligand(s). Numerous changes in chemical and physical properties observed for the F64PcM compounds can be accounted for by the calculated results.
Condensed Matter, Interfaces, and Materials

Stability of K-Montmorillonite Hydrates: Hybrid MC Simulations
G. Odriozola - and
J. F. Aguilar
NPzzT and μPzzT simulations of K-montmorillonite hydrates were performed employing hybrid Monte Carlo simulations. Two condition sets were studied: P = 1 atm and T = 300 K (ground level conditions) and P = 600 atm and T = 394 K; this last condition mimics a burial depth close to 4 km. For these conditions, swelling curves as a function of the reservoir water vapor pressure were built. We found the single layer K-montmorillonite hydrate stable for high vapor pressures for both burial and ground level conditions. A simple explanation for this high stability is given.

Hydrogen Bond Properties and Dynamics of Liquid−Vapor Interfaces of Aqueous Methanol Solutions
Sandip Paul - and
Amalendu Chandra
The hydrogen bonded structure and dynamics of liquid−vapor interfaces of aqueous methanol solutions of varying compositions are investigated by means of molecular dynamics simulations. The dynamical aspects of the interfaces are investigated in terms of the single-particle dynamical properties such as the relaxation of velocity autocorrelation and the translational diffusion coefficients along the perpendicular and parallel directions and the dipole orientational relaxation of the interfacial water and methanol molecules and also in terms of the relaxation of water−water, water−methanol, and methanol−methanol hydrogen bonds at interfaces at 298 K. The results of the interfacial dynamics are compared with those of the corresponding bulk phases. The inhomogeneous density, anisotropic orientational profiles, surface tension, and the pattern of hydrogen bonding are calculated in order to characterize the location, width, microscopic structure, and the thermodynamic aspects of the interfaces and to explore their effects on the interfacial dynamical properties of water and methanol molecules.
Nanochemistry

Modeling Proton Transfer in Zeolites: Convergence Behavior of Embedded and Constrained Cluster Calculations
Justin T. Fermann - ,
Teresa Moniz - ,
Oliver Kiowski - ,
Timothy J. McIntire - ,
Scott M. Auerbach - ,
Thom Vreven - , and
Michael J. Frisch
We have studied the convergence properties of embedded and constrained cluster models of proton transfer in zeolites. We applied density functional theory to describe clusters and ONIOM to perform the embedding. We focused on converging the reaction energy and barrier of the O(1) to O(4) jump in H−Y zeolite as well as vibrational and structural aspects of this jump. We found that using successively larger clusters in vacuo gives convergence of this reaction energy to 14 ± 2 kJ mol-1 and the barrier to 135 ± 5 kJ mol-1 at a cluster size of 5 Å, which contains 11 tetrahedral (Si or Al) atoms. We embedded quantum clusters of various sizes in larger clusters with total radii in the range 7−20 Å, using the universal force field as the lower level of theory in ONIOM. We found convergence to the same values as the constrained clusters, without the use of reactive force fields or periodic boundary conditions in the embedding procedure. For the reaction energy, embedded cluster calculations required smaller clusters than in vacuo calculations, reaching converged reaction energies for quantum systems containing at least 8 tetrahedral atoms. In addition, optimizations on embedded clusters required many fewer cycles, and hence much less CPU time, than did optimizations on comparable constrained clusters.
Biomolecular Systems

Accurate QM/MM Free Energy Calculations of Enzyme Reactions: Methylation by Catechol O-Methyltransferase
Thomas H. Rod - and
Ulf Ryde
We recently described a method to compute accurate quantum mechanical free energies [Rod, T. H.; Ryde, U. Phys. Rev. Lett. 2005, 94, 138302]. The method, which we term quantum mechanical thermodynamic cycle perturbation (QTCP), employs a molecular mechanics force field to sample phase space and, subsequently, a thermodynamic cycle to estimate QM/MM free energy changes. Here, we discuss the methodology in detail and test an approach based on a different thermodynamic cycle. We also show that a new way of treating hydrogen link atoms makes the free energy changes converge faster and that extrapolation to higher accuracy can be performed. We finally discuss the quantum mechanical free energy (QM/MM-FE) method in the framework of the QTCP method. All methods considered are applied to the methylation of catecholate catalyzed by catechol O-methyltransferase. We compute the free energy barrier for the reaction by computing free energy changes in steps between fixed QM regions along a predetermined reaction pathway. Using the QTCP approach, an extrapolated activation free energy of 69 kJ/mol for the forward reaction and 90 kJ/mol for the reverse reaction are obtained at the level of the B3LYP functional and the 6-311++G(2d,2p) basis set. The value for the forward reaction is in excellent agreement with the experimental value of 75 kJ/mol. Results based on the QM/MM-FE method differ by less than 10 kJ/mol from those values, indicating that QM/MM-FE may be a fairly accurate and cheap alternative to calculate QM/MM free energy changes. Moreover, the results are compared to barriers obtained with a fixed molecular mechanics environment as well as with structures optimized in a vacuum. All the computed free energy barriers are well converged. A major approximation in the current implementation of the QTCP method is that the QM region is fixed. The approximation leads to well-converged free energy barriers, which has been a problem in similar studies.

Helix Interactions in Membranes: Lessons from Unrestrained Monte Carlo Simulations
Yana A. Vereshaga - ,
Pavel E. Volynsky - ,
Dmitry E. Nolde - ,
Alexander S. Arseniev - , and
Roman G. Efremov
We describe one of the first attempts at unrestrained modeling of self-association of α-helices in implicit heterogeneous membrane-mimic media. The computational approach is based on the Monte Carlo conformational search for peptides in dihedral angles space. The membrane is approximated by an effective potential. The method is tested in calculations of two hydrophobic segments of human glycophorin A (GpA), known to form membrane-spanning dimers in real lipid bilayers. Our main findings may be summarized as follows. Modeling in vacuo does not adequately describe the behavior of GpA helices, failing to reproduce experimental structural data. The membrane environment stabilizes α-helical conformation of GpA monomers, inducing their transmembrane insertion and facilitating interhelical contacts. The voltage difference across the membrane promotes “head-to-head” orientation of the helices. “Fine-tuning” of the monomers in a complex is shown to be regulated by van der Waals interactions. Detailed exploration of conformational space of the system starting from arbitrary locations of two noninteracting helices reveals only several groups of energetically favorable structures. All of them represent tightly packed transmembrane helical dimers. In overall, they agree reasonably well with mutagenesis data, some of them are close to NMR-derived structures. A possibility of left-handed dimers is discussed. We assume that the observed moderate structural heterogeneity (the existence of several groups of states with close energies) reflects a real equilibrium dynamics of the monomersat least in membrane mimics used in experimental studies of GpA. The elaborated computational approach is universal and may be employed in studies of a wide class of membrane peptides and proteins.

Quantum Mechanics/Molecular Mechanics Calculations of the Vanadium Dependent Chloroperoxidase
Joslyn Yudenfreund Kravitz - ,
Vincent L. Pecoraro - , and
Heather A. Carlson
Large quantum mechanics/molecular mechanics (QM/MM) calculations are used to probe the resting and initial protonated states of the vanadium dependent chloroperoxidase from the pathogenic fungus Curvularia inaequalis. QSite was used to model 433 residues and 24 structural waters with molecular mechanics, while 8 active-site residues and the vanadate cofactor (161 atoms) were represented at the B3LYP/lacvp* level of theory. Our previous study of small model systems implied that the resting state of the enzyme contains a trigonal bipyramidal vanadate with one hydroxyl group in the equatorial plane and another in the axial position. This study uses a much larger model of the biological system at a higher level of theory to identify the location of the equatorial hydroxo group with respect to the enzyme active site. We also identify a second resting-state configuration with an axial water and three equatorial oxo moieties that is nearly isoenergetic with the previously identified state. We propose that the resting state is a hybrid of these two configurations, stabilized by the long-range electrostatic field of the protein environment. The first step in catalysis is believed to be protonation of the vanadate. Our previous small models indicated that there were two protonated configurations, but this study shows that the configuration containing an axial water and one hydroxo group in the equatorial plane is significantly lower in energy than any other configuration. Additionally, we can now assign an important role for lysine 353 in the catalytic cycle. Based on our calculations and other model studies, we provide an updated catalytic cycle for vanadium dependent haloperoxidase activity. Further, we demonstrate the importance of system set up. In particular, maintaining the proper electrostatic field at the active site is crucial for identifying the correct minima in a truncated protein model.

A Semiempirical Quantum Model for Hydrogen-Bonded Nucleic Acid Base Pairs
Timothy J. Giese - ,
Edward C. Sherer - ,
Christopher J. Cramer - , and
Darrin M. York
An exploratory semiempirical Hamiltonian (PM3BP) is developed to model hydrogen bonding in nucleic acid base pairs. The PM3BP Hamiltonian is a novel reparametrization of the PM3 Hamiltonian designed to reproduce experimental base pair dimer enthalpies and high-level density-functional results. The parametrization utilized a suite of integrated nonlinear optimization algorithms interfaced with a d-orbital semiempirical program. Results are compared with experimental values and with benchmark density-functional (mPWPW91/MIDI!) calculations for hydrogen-bonded nucleic acid dimers and trimers. The PM3BP Hamiltonian is demonstrated to outperform the AM1, PM3, MNDO, and MNDO/H Hamiltonians for dimer and trimer structures and interaction enthalpies and is shown to reproduce experimental dimer interaction enthalpies that rival density-functional results for an over 3 orders of magnitude reduction in computational cost. The tradeoff between a high accuracy gain for hydrogen bonding at the expense of sacrificing some generality is discussed. These results provide insight into the limits of conventional semiempirical forms for accurate modeling of biological interactions.

Effects of Calcium Binding on Structure and Autolysis Regulation in Trypsins. A Molecular Dynamics Investigation
Elena Papaleo - ,
Piercarlo Fantucci - , and
Luca De Gioia
The calcium ion was proposed to be involved in protein structure stabilization against thermal and proteolytic degradation, such as autolysis phenomena, in trypsin-like serine proteases. However, molecular details related to the role played by the metal ion are still largely unknown. Several molecular dynamics simulations of 6 ns have been used to investigate the dynamic behavior of bovine and salmon trypsins in calcium-bound and calcium-free forms, with the aim of evaluating the role of the calcium ion in trypsin three-dimensional structure and autoproteolysis propensity. It turned out that the calcium-free trypsins are characterized by a more flexible structure, revealing structure−function relationships connecting Ca2+ binding and autoproteolysis propensity. In particular, the removal of Ca2+ not only increases the flexibility of regions around its binding site, in the N-terminal domain, but also leads to channeling of the fluctuations to remote sites in the C-terminal domain, possibly involving the interdomain loop. Two primary autolysis sites are strongly influenced by calcium binding (R117 and K188) in bovine trypsin, whereas Ca2+ plays a less crucial role in salmon trypsin.
Structure Prediction

Theoretical Group 14 Chemistry. 4. Cyclotriplumbanes: Relativistic and Substituents Effects
Rainer Koch - ,
Torsten Bruhn - , and
Manfred Weidenbruch
We report a study on the first newly synthesized homonuclear lead ring system, the cyclotriplumbane Pb3R6. Its geometrical features can be best reproduced using perturbation theory (MP2) together with the Stuttgart-Dresden basis set and ECP for lead. The experimentally observed tilting of the groups R in the cyclotriplumbanes is attributed to the bonding situation: the lead−lead contacts, formed from weak interactions of plumbylene lone pairs with empty p orbitals of neighboring lead atoms, try to maximize overlap. Surprisingly and in contrast to the inert pair effect, hybridization of the former plumbylene lone pair orbitals in the cyclotriplumbane Pb3R6 is observed, depending on the substituent. Hybrid orbitals with a 6s orbital contribution of only about 40% are found. Hydrogen atoms and methyl groups promote this effect, while for phenyl substitution the expected 6s lone pair orbital is identified as the bond-forming orbital.

PELE: Protein Energy Landscape Exploration. A Novel Monte Carlo Based Technique
Kenneth W. Borrelli - ,
Andreas Vitalis - ,
Raul Alcantara - , and
Victor Guallar
Combining protein structure prediction algorithms and Metropolis Monte Carlo techniques, we provide a novel method to explore all-atom energy landscapes. The core of the technique is based on a steered localized perturbation followed by side-chain sampling as well as minimization cycles. The algorithm and its application to ligand diffusion are presented here. Ligand exit pathways are successfully modeled for different systems containing ligands of various sizes: carbon monoxide in myoglobin, camphor in cytochrome P450cam, and palmitic acid in the intestinal fatty-acid-binding protein. These initial applications reveal the potential of this new technique in mapping millisecond-time-scale processes. The computational cost associated with the exploration is significantly less than that of conventional MD simulations.