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Research ArticleFebruary 21, 2017

Construction of a Chassis for a Tripartite Protein-Based Molecular Motor
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ACS Synthetic Biology

Cite this: ACS Synth. Biol. 2017, 6, 6, 1096–1102

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https://doi.org/10.1021/acssynbio.7b00037

Published February 21, 2017

Abstract

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Improving our understanding of biological motors, both to fully comprehend their activities in vital processes, and to exploit their impressive abilities for use in bionanotechnology, is highly desirable. One means of understanding these systems is through the production of synthetic molecular motors. We demonstrate the use of orthogonal coiled-coil dimers (including both parallel and antiparallel coiled coils) as a hub for linking other components of a previously described synthetic molecular motor, the Tumbleweed. We use circular dichroism, analytical ultracentrifugation, dynamic light scattering, and disulfide rearrangement studies to demonstrate the ability of this six-peptide set to form the structure designed for the Tumbleweed motor. The successful formation of a suitable hub structure is both a test of the transferability of design rules for protein folding as well as an important step in the production of a synthetic protein-based molecular motor.

Subjects

Protein-based molecular machines are a vital component of living cells and carry out diverse functions including the transportation of numerous cargoes, muscle contraction, and cell division. (1, 2) Biological motors are highly complex, regulated machines, making them challenging to study but also a motivating target for use in bionanotechnology. (3, 4) Within the field of synthetic biology, the bottom-up approach (5, 6) aims to start with simplified, well-characterized, components and modify or extend their functionality, in this case to produce novel nanoscale motors. A key design challenge in this area is the level of reproducibility and transferability of components from one context to another, and determining the ability of components to be combined without unexpected interactions occurring is important.

Entirely synthetic, biologically inspired motors have been designed with varying levels of ability and mimicry, including small molecule machines such as switches, shuttles, and even a robotic arm. (7, 8) Using more biological starting materials, there has also been significant progress in the field of autonomous DNA motors (9, 10) and hybrid DNA–protein motors. (11) Neither of these areas, however, utilize the same set of initial building blocks as nature: amino acids. The field of synthetic protein motors is far less developed due to the higher complexity of amino acid interactions. There are, however, several examples of combining peptides with small molecules to create synthetic machines (12-14) and structures such as a cyclic peptide-based nanopore, (15) but there are, to our knowledge, no peptide or protein-based synthetic motors that avoid the use of existing protein motor domains.

This paper describes progress in the realization of a series of previously published motor designs, including the Tumbleweed and SKIP motors. (16, 17) These motors are designed to undergo directed motion through rectified diffusion using ligand-controlled binding of their “feet” to a DNA track. A peptide “hub” is proposed (16) to self-assemble, connect, and organize E. coli protein based “feet” with the ability to bind orthogonal DNA sequences (in the presence of orthogonal ligands) to form the motor molecule (see Figure 1). Construction of a suitable DNA track (18) and microfluidic device (19, 20) have since been demonstrated, along with further simulation studies. (21, 22)

Figure 1. “Y” configuration of the Tumbleweed Hub. The peptide hub termini are indicated, showing the parallel coiled coils p1,p2 and p3,p4, and the antiparallel coiled coil p5,p6. To form a hub, coiled-coil pairs (p1,p2), (p3,p4), and (p5,p6) need to preferentially interact, while p1 and p6, p2 and p3, and p4 and p5 are covalently linked, to ensure that all of the coiled coils are connected to form one structure. The nonhelical central ribbons represent the residues at one end of every peptide that are designed not to contribute to a coiled-coil region. Figure adapted with permission from ref 22. Copyright 2011 American Physical Society.

The proposed hub is composed of three peptide sequences, each of which contains two coiled-coil domains, (23) with each domain programmed to assemble with a specified partner to produce the final configuration (see Figure 1). Coiled-coil domains have been selected for this application, primarily due to their ability to undergo programmed assembly; however, the rigidity of the folded domain is also desirable in reducing the probability of backward stepping and hence improving the efficiency of the final motor. The use of coiled-coils in this way is not straightforward as individual coiled-coil sequences have often been found to interact with many other potential partners rather than interacting only with their biologically relevant partner. (24, 25) It has also been documented in other areas of synthetic biology that once the complexity of synthetic systems increases, unintended cross-talk between components can occur. (26, 27)

To design the high fidelity sequences required in this application we must therefore draw on the wealth of information now available on the folding and interactions of coiled coils. (23, 28, 29) The coiled-coil nanostructure field has advanced on many fronts in recent years including the use of biological coiled-coil domains in novel combinations, (30, 31) the design of self-assembling peptides from first-principles, (32-34) and the use of computational design tools. (35-37) From these works we anticipate the need to use a heptad repeat of hydrophobic residues with polar insertions used to specify the orientation of helix interactions. Given that our peptides will each contain two coiled-coil domains, we must consider the formation of intramolecular hairpins to be a primary route to misfolding and use the combination of charged amino acids and polar insertions to the hydrophobic core to specifically design against this eventuality in each peptide. In addition to the coiled-coil oligomerization information, knowledge on how to link domains successfully must be extracted from recent studies (38, 39) and applied in order to provide sufficient flexibility between domains to allow folding.

In this work we have designed, synthesized, and characterized a linked system of three coiled coils, suitable for the formation of a hub for the Tumbleweed motor. The design in this work is presented as a proof of principle that the combined knowledge within the field can be successfully applied to a range of new applications requiring the ordered colocalization of multiple functional components, including the design of hubs for protein-based synthetic molecular motors.

Results and Discussion

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Using the design principles laid out previously (38, 40) six peptides were designed to form three dimeric coiled coils: (p1,p2), (p3,p4), and (p5,p6). Polar residues are included in various hydrophobic core positions to prevent staggered assembly and electrostatic interactions are optimized to produce the desired dimeric pairings using an algorithm reported previously. (40) All contain a tyrosine residue for UV absorption concentration measurements, a single cysteine residue for disulfide bond formation, and a linker of glycine and asparagine intended to form a flexible region outside the coiled-coil domains on one terminus.

The sequences of the six peptides labeled in Figure 1 are shown in Table 1. These were synthesized using solid phase peptide synthesis and purified with high performance liquid chromatography. Several facts must be established in order to confirm the success of the design principles and demonstrate that when all six peptides are mixed, the three required dimeric coiled-coil structures are produced. First we must demonstrate that the designed peptide pairs interact with each other. Second we must show that the structures formed by these pairs are dimeric in nature. Finally we must find that the three designed pairs are produced preferentially over other possible oligomers.

Table 1

The secondary structures of the peptides and two-peptide combinations were studied with circular dichroism (CD). The individual peptides displayed varying levels of helicity (see Figure S1a). All 15 two-peptide mixtures were made and measured. The CD spectra of the three specified dimers, alongside the spectra of the component peptides, are shown in Figure 2 panels a, b, and c. All three pairs indicate the presence of heterooligomeric interactions, as the measured spectra of the mixtures show greater helicity than those predicted from the sum of the individual component peptide spectra. The data from the other 12 possible combinations of two hub peptides also demonstrate various levels of heterooligomeric interactions to be present. These data show that the specified pairs can be formed. To determine whether the desired pairs are formed preferentially to other interactions, all six peptides were mixed together. The CD spectrum of this mixture is shown in Figure 2d. This has been compared to predicted spectra for six noninteracting species, and to a sample comprising only the three designed pairs. As expected, the combined spectrum is highly similar to that predicted under the assumption that no further interactions are produced when the designed pairs are mixed.

Figure 2. CD spectra of the three mixtures of the designed pairs of peptides: (a) p1 and p2, (b) p3 and p4, and (c) p5 and p6 (shown in green). Each panel also shows the individual peptide spectra (red and blue, in numerical order), and the theoretical signal for a mixture of the two without interaction (a combination of the two single peptide signals, shown in purple). (d) CD spectrum of all six hub peptides mixed together (green), compared with the theoretical spectrum predicted from the individual spectra (shown in magenta), and from the designed pair spectra (shown in purple). Each sample had a concentration of 20 μM per peptide, in PBS buffer (pH 7.4), measured at 20 °C. Dotted lines represent the wavelength cutoff below which data cannot be reliably obtained, as dictated by the CD instrument.

Analytical ultracentrifugation (AUC) measurements of the designed coiled-coil pairs (Table 2) gave molecular weights consistent with dimer formation, and inconsistent with monomers or oligomers of a higher order than dimers (see Supporting Information, Tables S1 and S2 for further details).

Table 2

sample	expected molecular weight/Da	measured molecular weight/Da
p1,p2	7041	7000 ± 1000
p3,p4	7397	7100 ± 1000
p5,p6	5816	5900 ± 1000

Likewise, dynamic light scattering (DLS) measurements of the designed coiled-coil pairs each exhibited species with 3–5 nm hydrodynamic diameters, consistent with the hypothesis of the formation of discrete coiled-coil oligomers, and inconsistent with the formation of fibers (Figure S2).

To demonstrate the fidelity of the interactions and to confirm the utility of the peptides in organizing the motor hub, pairs of the peptides were covalently linked using a disulfide bond between terminal cysteine residues, and the disulfide-bonded peptides, p6–p1, p3–p2, and p4–p5 were produced and characterized.

The CD spectra of the disulfide-bonded peptides reveal little about the system as all of the collected spectra show high levels of helicity (see SI Figure S1b). This is expected for a system where the peptides have been designed to form coiled-coils and have been colocalized by the disulfide tethering causing conditions of high local concentration and hence nonspecific coiled-coil formation.

AUC results are more informative about the system’s interactions (see Table 3). The single disulfide-bonded peptides have the expected masses. (The higher than expected value found for p2–p3 nonetheless corresponds well to a single species fit, and the mass found is far closer to the mass of a single disulfide-bonded peptide than to a pair.) To study the specificity of coiled-coil interactions, the disulfide-bonded peptides were mixed pairwise and allowed to associate. The mixtures of pairs of disulfide-bonded peptides exhibit single species behavior, indicative of the desired specificity of interaction. Furthermore, this species in each case has a mass consistent with the interaction of two disulfide-bonded peptides. The mixture of all three disulfide-bonded peptides gives a mass consistent with the expected mass of 20 248 Da, again supportive of our design criteria.

Table 3

sample	expected heterodimeric molecular weight/Da	measured molecular weight/Da
p6–p1	6470	7300 ± 1000
p2–p3	7096	9700 ± 1000
p4–p5	6682	7600 ± 1000
p6–p1, p2–p3	13566	16000 ± 1000
p2–p3, p4–p5	13778	14000 ± 1000
p4–p5, p6–p1	13151	16000 ± 1000
p6–p1, p2–p3, p4–p5	20248	19000 ± 1000

DLS data of the individual disulfide-bonded peptides gave hydrodynamic diameters of 3–4 nm, while DLS data of pairs of the disulfide-bonded peptides, and of all three disulfide-bonded peptides mixed, showed a shift to higher values, around 5 nm (see Figure S3). The change in size between the single and pairs of disulfide-bonded peptides indicates that there is interaction between the disulfide-bonded peptides. The fact that the size of the three-component mixture is similar to that of the pairs of disulfide-bonded peptides is supportive that a structure such as that shown in Figure 1 is formed, and not a lengthy fiber.

To further verify that the interactions occurring in the final structure are due to the three specified peptide pairs, we carried out disulfide exchange experiments on the linked peptides. We measured the system of three disulfide-bonded peptides, and then changed the system’s redox potential, using reduced glutathione, to allow the disulfide bonds to rearrange. If there are preferred interactions, the disulfide bonds formed when rearrangement is possible should reflect these preferences (see Figure 3). We measured the species in each of these samples using MALDI-ToF mass spectrometry, and the results are shown in Figure 4. Prior to rearrangement, the species present in the system are the disulfide-bonded peptides produced in the laboratory (see Figure 4a). Once the disulfide bonds are given the opportunity to rearrange (see Figure 4b), the species present change. Disulfide-bonded versions of all three of the designed pairs (p1–p2, p3–p4, p6–p5) produce the dominant peaks, along with a fourth peak attributed to the starting peptide 2–3 (that is likely due to a failure to produce a precise 1:1:1 ratio of the starting species). Regardless of the presence of this peak, it is clear that the three designed pairs interact when given the opportunity, while none of the other possible combinations not present in the initial system form during rearrangement (Supporting Information Table S3 for details of peak assignments).

Figure 3. If the designed dimer peptides preferentially interact, when allowed to rearrange, the disulfide bonds should switch to being between the desired pairs, with the species present in the system moving from p6–p1, p3–p2, and p4–p5 to p1–p2, p3–p4, and p5–p6.

Figure 4. MALDI spectra of glutathione experiments. The initial spectrum has prominent peaks due to the p4–p5 (MW 6682 Da) and p3–p2 (MW 7095 Da) species, and smaller peaks due to deletions and the p6–p1 peptide (MW 6470 Da). After rearrangement, the p4–p5 and p6–p1 species are no longer seen, while the p6–p5 (MW 5814 Da), p1–p2 (MW 7039 Da) and p3–p4 (MW 7395 Da) species have appeared. All of the trace peaks correlate with impurities in the initial samples and do not correlate with possible rearrangements.

This combined information from CD, DLS, AUC, and disulfide rearrangement experiments indicates that the hub construction should indeed be possible from mixing covalently linked species of peptides p1 and p6, p2 and p3, and p4 and p5, driven by coiled-coil interactions. As such, this has been a successful test of the hypothesis that the knowledge within the peptide design field is now sufficient for the design of self-assembling hubs for diverse applications, including the colocalization of other motor components.

Future extensions of this work could investigate whether it is possible to combine this synthetic biology approach to structure design with active means of actuating the structure. Using the observed ability of peptides (41-43) to switch conformation in different conditions could provide a feasible means of adapting this system to undergo conformational changes (and hence changes in movement) in the presence of different stimuli. This will take us one step closer to realizing designed protein motion.

Conclusions

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We have demonstrated that a set of six coiled-coil domains can be designed to self-assemble preferentially into three coiled-coil heterodimers. We have shown that by pairing the domains covalently, a hub structure can be formed. This hub can then be used to assemble multiple functional units into the desired 3D configuration. We propose using this technology to produce designed protein motor hubs; however, the methodology exploited here may have wider applications in the design and production of self-assembling junctions in other areas of bionanotechnology including the construction of synthetic cages or other nanoscale devices.

Materials and Methods

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Amino acids and PyBOP were purchased from AGTC Bioproducts Ltd. DMF was purchased from Rathburn Chemicals and AGTC Bioproducts Ltd. Rink amide MBHA resin was purchased from Novabiochem. Other synthesis materials, including Aldrithiol-2, were purchased from Sigma-Aldrich. HPLC grade acetonitrile was purchased from Fisher Scientific.

Peptides were synthesized using SPPS using a CEM Liberty 1 peptide synthesizer under standard conditions. HPLC purification was carried out using linear water to acetonitrile gradients, with a PerkinElmer 785A detector and Series 200 LC pump, and a C₁₈ column. MALDI-ToF experiments were carried out using a Bruker Daltonics Autoflex II ToF/ToF machine, and α-cyano-4-hydroxycinnamic acid matrix.

To form each disulfide-bonded peptide, one of the contributing peptides (dissolved in water) was reacted with a 10-fold excess of Aldrithiol-2 (in acetonitrile), and the products were separated by HPLC. The peptide product was then reacted with the other contributing peptide, and through displacement formed a disulfide-bonded peptide. The waste products of this reaction were then removed using HPLC.

Concentrations were determined using UV–vis absorption spectroscopy, and the tyrosine absorption centered around 276 nm: ε_Tyr = 1280 cm^–1 mol^–1. With the exception of UV–vis spectra for the disulfide exchange experiments, which used a Thermo Scientific Nanodrop 1000, spectra were taken using a Unicam UV2 spectrometer.

CD spectroscopy was carried out using a JASCO J-1500 spectropolarimeter with mini-circulation bath and Peltier stage, using a 1 mm quartz cuvette. Samples were made at a concentration of 20 μM per peptide, in PBS buffer.

AUC sedimentation equilibrium data was collected at 20 °C in PBS buffer using a Beckman Optima XL-I analytical ultracentrifuge with an An-60 Ti rotor. The partial specific volume for each of the peptides/peptide mixtures, and the solvent density, were calculated using Sednterp.

DLS measurements were taken on a Malvern Zetasizer μV using Sarstedt disposable transparent cuvettes. Samples were made at a concentration of 100 μM per peptide, in PBS buffer.

TFA in water solutions (pH 2) were found to quench the disulfide exchange reaction, and hence this was used to both prevent rearrangement of the initial species prior to MALDI analysis, and to quench the system after rearrangement was encouraged in a second sample. Each of the disulfide-bonded peptides, in water solution, was added to both a solution of TFA in water (4 μL TFA in 15 mL water, pH 2) and to a PBS buffer solution containing reduced glutathione. After 10 min, TFA in water was added to the glutathione-containing solution to quench the reaction. These two solutions were then studied using MALDI-ToF mass spectrometry.

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssynbio.7b00037.

Additional circular dichroism data; dynamic light scattering data; AUC fitting information; MALDI data (PDF)

sb7b00037_si_001.pdf (268.15 kb)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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Corresponding Author
- Elizabeth H. C. Bromley - Department of Physics, Durham University, Durham, DH1 3LE, United Kingdom; http://orcid.org/0000-0002-7678-1187; Email: [email protected]
Authors
- Lara S. R. Small - Department of Physics, Durham University, Durham, DH1 3LE, United Kingdom
- Marc Bruning - School of Chemistry, University of Bristol, BS8 1TS, Bristol, United Kingdom
- Andrew R. Thomson - School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, United Kingdom
- Aimee L. Boyle - Faculty of Science, Leiden Institute of Chemistry, Leiden, 2333 CC, Netherlands
- Roberta B. Davies - Structural Biology Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia
- Paul M. G. Curmi - School of Physics, University of New South Wales, Sydney, New South Wales 2052, Australia
- Nancy R. Forde - Department of Physics, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
- Heiner Linke - NanoLund and Solid State Physics, Lund University, Box 118, 22100 Lund, Sweden
- Derek N. Woolfson - School of Chemistry, University of Bristol, BS8 1TS, Bristol, United Kingdom; School of Biochemistry, University of Bristol, BS8 1TD, Bristol, United Kingdom; BrisSynBio, Life Sciences Building, University of Bristol, BS8 1TQ, Bristol, United Kingdom; http://orcid.org/0000-0002-0394-3202
Notes
The authors declare no competing financial interest.

Acknowledgment

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The authors thank EPSRC for funding L.S.R.S. through a Doctoral Studentship (EP/P505488/1) and Doctoral Prize (EP/M507854/1). A.R.T. and D.N.W. are supported by the ERC (340764), and D.N.W. is a Royal Society Wolfson Research Merit Award holder (WM140008). H.L. is supported by a Swedish Research Council Grant 2015-0612. Data supporting this article is available at http://dx.doi.org/10.15128/r2qr46r080t.

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Chen, Yuan-Jyue; Groves, Benjamin; Muscat, Richard A.; Seelig, Georg
Nature Nanotechnology (2015), 10 (9), 748-760CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
A review. The programmability of Watson-Crick base pairing, combined with a decrease in the cost of synthesis, has made DNA a widely used material for the assembly of mol. structures and dynamic mol. devices. Working in cell-free settings, researchers in DNA nanotechnol. have been able to scale up system complexity and quant. characterize reaction mechanisms to an extent that is infeasible for engineered gene circuits or other cell-based technologies. However, the most intriguing applications of DNA nanotechnol. - applications that best take advantage of the small size, biocompatibility and programmability of DNA-based systems - lie at the interface with biol. Here, we review recent progress in the transition of DNA nanotechnol. from the test tube to the cell. We highlight key successes in the development of DNA-based imaging probes, prototypes of smart therapeutics and drug delivery systems, and explore the future challenges and opportunities for cellular DNA nanotechnol.
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Pan, J., Li, F. R., Cha, T. G., Chen, H. R., and Choi, J. H. (2015) Recent progress on DNA based walkers Curr. Opin. Biotechnol. 34, 56– 64 DOI: 10.1016/j.copbio.2014.11.017
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Recent progress on DNA based walkers
Pan, Jing; Li, Feiran; Cha, Tae-Gon; Chen, Haorong; Choi, Jong Hyun
Current Opinion in Biotechnology (2015), 34 (), 56-64CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
A review. DNA based synthetic mol. walkers are reminiscent of biol. protein motors. They are powered by hybridization with fuel strands, environment induced conformational transitions, and covalent chem. of oligonucleotides. Recent developments in exptl. techniques enable direct observation of individual walkers with high temporal and spatial resoln. The functionalities of state-of-the-art DNA walker systems can thus be analyzed for various applications. Herein we review recent progress on DNA walker principles and characterization methods, and evaluate various aspects of their functions for future applications.
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Lund, K., Manzo, A. J., Dabby, N., Michelotti, N., Johnson-Buck, A., Nangreave, J., Taylor, S., Pei, R. J., Stojanovic, M. N., and Walter, N. G. 2010, Molecular robots guided by prescriptive landscapes Nature 465, 206– 210 DOI: 10.1038/nature09012
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Molecular robots guided by prescriptive landscapes
Lund, Kyle; Manzo, Anthony J.; Dabby, Nadine; Michelotti, Nicole; Johnson-Buck, Alexander; Nangreave, Jeanette; Taylor, Steven; Pei, Renjun; Stojanovic, Milan N.; Walter, Nils G.; Winfree, Erik; Yan, Hao
Nature (London, United Kingdom) (2010), 465 (7295), 206-210CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
Traditional robots rely for their function on computing, to store internal representations of their goals and environment and to coordinate sensing and any actuation of components required in response. Moving robotics to the single-mol. level is possible in principle, but requires facing the limited ability of individual mols. to store complex information and programs. One strategy to overcome this problem is to use systems that can obtain complex behavior from the interaction of simple robots with their environment. A first step in this direction was the development of DNA walkers, which have developed from being non-autonomous to being capable of directed but brief motion on one-dimensional tracks. Here we demonstrate that previously developed random walkers--so-called mol. spiders that comprise a streptavidin mol. as an inert 'body' and three deoxyribozymes as catalytic 'legs'--show elementary robotic behavior when interacting with a precisely defined environment. Single-mol. microscopy observations confirm that such walkers achieve directional movement by sensing and modifying tracks of substrate mols. laid out on a two-dimensional DNA origami landscape. When using appropriately designed DNA origami, the mol. spiders autonomously carry out sequences of actions such as 'start', 'follow', 'turn' and 'stop'. We anticipate that this strategy will result in more complex robotic behavior at the mol. level if addnl. control mechanisms are incorporated. One example might be interactions between multiple mol. robots leading to collective behavior; another might be the ability to read and transform secondary cues on the DNA origami landscape as a means of implementing Turing-universal algorithmic behavior.
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Ikezoe, Y., Fang, J., Wasik, T. L., Shi, M. L., Uemura, T., Kitagawa, S., and Matsui, H. (2015) Peptide-Metal Organic Framework Swimmers that Direct the Motion toward Chemical Targets Nano Lett. 15, 4019– 4023 DOI: 10.1021/acs.nanolett.5b00969
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Peptide-Metal Organic Framework Swimmers that Direct the Motion toward Chemical Targets
Ikezoe, Yasuhiro; Fang, Justin; Wasik, Tomasz L.; Shi, Menglu; Uemura, Takashi; Kitagawa, Susumu; Matsui, Hiroshi
Nano Letters (2015), 15 (6), 4019-4023CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
Highly efficient and robust chem. motors are expected for the application in microbots that can selectively swim toward targets and accomplish their tasks in sensing, labeling, and delivering. However, one of major issues for such development is that current artificial swimmers have difficulty controlling their directional motion toward targets like bacterial chemotaxis. To program synthetic motors with sensing capability for the target-directed motion, we need to develop swimmers whose motions are sensitive to chem. gradients in environments. Here we create a new intelligent biochem. swimmer by integrating metal org. frameworks (MOFs) and peptides that can sense toxic heavy metals in soln. and swim toward the targets. With the aid of Pb-binding enzymes, the peptide-MOF motor can directionally swim toward PbSe quantum dots (QD) by sensing pH gradient and eventually complete the motion as the swimmer reaches the highest gradient point at the target position in soln. This type of technol. could be evolved to miniaturize chem. robotic systems that sense target chems. and swim toward target locations.
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Ikezoe, Y., Washino, G., Uemura, T., Kitagawa, S., and Matsui, H. (2012) Autonomous motors of a metal-organic framework powered by reorganization of self-assembled peptides at interfaces Nat. Mater. 11, 1081– 1085 DOI: 10.1038/nmat3461
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Autonomous motors of a metal-organic framework powered by reorganization of self-assembled peptides at interfaces
Ikezoe, Yasuhiro; Washino, Gosuke; Uemura, Takashi; Kitagawa, Susumu; Matsui, Hiroshi
Nature Materials (2012), 11 (12), 1081-1085CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
A variety of microsystems have been developed that harness energy and convert it to mech. motion. Here we have developed new autonomous biochem. motors by integrating a metal-org. framework (MOF) and self-assembling peptides. The MOF is applied as an energy-storing cell that assembles peptides inside nanoscale pores of the coordination framework. The nature of peptides enables their assemblies to be reconfigured at the water/MOF interface, and thus converted to fuel energy. Reorganization of hydrophobic peptides can create a large surface-tension gradient around the MOF that can efficiently power its translational motion. As a comparison, the velocity normalized by vol. for the diphenylalanine-MOF particle is faster and the kinetic energy per unit mass of fuel is more than twice as great as that for previous gel motor systems. This demonstration opens the route towards new applications of MOFs and reconfigurable mol. self-assembly, possibly evolving into a smart autonomous motor capable of mimicking swimming bacteria, and with integrated recognition units, harvesting target chems.
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Nagatsugi, F., Takahashi, Y., Kobayashi, M., Kuwahara, S., Kusano, S., Chikuni, T., Hagihara, S., and Harada, N. (2013) Synthesis of peptide-conjugated light-driven molecular motors and evaluation of their DNA-binding properties Mol. BioSyst. 9, 969– 973 DOI: 10.1039/c2mb25520k
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Synthesis of peptide-conjugated light-driven molecular motors and evaluation of their DNA-binding properties
Nagatsugi, Fumi; Takahashi, Yusuke; Kobayashi, Maiko; Kuwahara, Shunsuke; Kusano, Shuhei; Chikuni, Tomoko; Hagihara, Shinya; Harada, Nobuyuki
Molecular BioSystems (2013), 9 (5), 969-973CODEN: MBOIBW; ISSN:1742-2051. (Royal Society of Chemistry)
Synthetic light-driven mol. motors are mol. machines capable of rotation under photo-irradn. In this paper, the authors report the synthesis of peptide-conjugated mol. motors and evaluate their DNA-binding properties.
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Watson, M. A. and Cockroft, S. L. (2016) Man-made molecular machines: membrane bound Chem. Soc. Rev. 45, 6118 DOI: 10.1039/C5CS00874C
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Man-made molecular machines: membrane bound
Watson, Matthew A.; Cockroft, Scott L.
Chemical Society Reviews (2016), 45 (22), 6118-6129CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
Nature's mol. machines are a const. source of inspiration to the chemist. Many of these mol. machines function within lipid membranes, allowing them to exploit potential gradients between spatially close, but chem. distinct environments to fuel their work cycle. Indeed, the realization of such principles in synthetic transmembrane systems remains a tantalising goal. This tutorial review opens by highlighting seminal examples of synthetic mol. machines. We illustrate the importance of surfaces for facilitating the extn. of work from mol. switches and motors. We chart the development of man-made transmembrane systems; from passive to machine-like stimuli-responsive channels, to fully autonomous transmembrane mol. machines. Finally, we highlight higher-order compartmentalised systems that exhibit emergent properties. We suggest that such higher-order architectures could serve as platforms for sophisticated devices that coordinate the activity of numerous transmembrane mol. machines.
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Bromley, E. H. C., Kuwada, N. J., Zuckermann, M. J., Donadini, R., Samii, L., Blab, G. A., Gemmen, G. J., Lopez, B. J., Curmi, P. M. G., and Forde, N. R. 2009, The Tumbleweed: towards a synthetic protein motor HFSP J. 3, 204– 212 DOI: 10.2976/1.3111282
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The Tumbleweed: toward a synthetic protein motor
Bromley, Elizabeth H. C.; Kuwada, Nathan J.; Zuckermann, Martin J.; Donadini, Roberta; Samii, Laleh; Blab, Gerhard A.; Gemmen, Gregory J.; Lopez, Benjamin J.; Curmi, Paul M. G.; Forde, Nancy R.; Woolfson, Derek N.; Linke, Heiner
HFSP Journal (2009), 3 (3), 204-212CODEN: HJFOA5; ISSN:1955-2068. (HFSP Publishing)
A review. Biomol. motors have inspired the design and construction of artificial nanoscale motors and machines based on nucleic acids, small mols., and inorg. nanostructures. However, the high degree of sophistication and efficiency of biomol. motors, as well as their specific biol. function, derives from the complexity afforded by protein building blocks. Here, we discuss a novel bottom-up approach to understanding biol. motors by considering the construction of synthetic protein motors. Specifically, we present a design for a synthetic protein motor that moves along a linear track, dubbed the "Tumbleweed.". This concept uses three discrete ligand-dependent DNA-binding domains to perform cyclically ligand-gated, rectified diffusion along a synthesized DNA mol. Here we describe how de novo peptide design and mol. biol. could be used to produce the Tumbleweed, and we explore the fundamental motor operation of such a design using numerical simulations. The construction of this and more sophisticated protein motors is an exciting challenge that is likely to enhance our understanding of the structure-function relationship in biol. motors.
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Zuckermann, M. J., Angstmann, C. N., Schmitt, R., Blab, G. A., Bromley, E. H. C., Forde, N. R., Linke, H., and Curmi, P. M. G. (2015) Motor properties from persistence: a linear molecular walker lacking spatial and temporal asymmetry New J. Phys. 17, 13 DOI: 10.1088/1367-2630/17/5/055017
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Kovacic, S., Samii, L., Woolfson, D. N., Curmi, P. M. G., Linke, H., Forde, N. R., and Blab, G. A. (2012) Design and Construction of a One- Dimensional DNA Track for an Artificial Molecular Motor J. Nanomater. 2012, 10 DOI: 10.1155/2012/109238
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Niman, C. S., Beech, J. P., Tegenfeldt, J. O., Curmi, P. M. G., Woolfson, D. N., Forde, N. R., and Linke, H. (2013) Controlled microfluidic switching in arbitrary time-sequences with low drag Lab Chip 13, 2389– 2396 DOI: 10.1039/c3lc50194a
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Controlled microfluidic switching in arbitrary time-sequences with low drag
Niman, Cassandra S.; Beech, Jason P.; Tegenfeldt, Jonas O.; Curmi, Paul M. G.; Woolfson, Derek N.; Forde, Nancy R.; Linke, Heiner
Lab on a Chip (2013), 13 (12), 2389-2396CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
The ability to test the response of cells and proteins to a changing biochem. environment is of interest for studies of fundamental cell physiol. and mol. interactions. In a common exptl. scheme the cells or mols. of interest are attached to a surface and the compn. of the surrounding fluid is changed. It is desirable to be able to switch several different biochem. reagents in any arbitrary order, and to keep the flow velocity low enough so that the cells and mols. remain attached and can be expected to retain their function. Here we develop a device with these capabilities, using U-shaped access channels. We use total-internal reflection fluorescence microscopy to characterize the time-dependent change in concn. during switching of solns. near the device surface. Well-defined fluid interfaces are formed in the immediate vicinity of the surface ensuring distinct switching events. We show that the exptl. data agrees well with Taylor-Aris theory in its range of validity. In addn., we find that well-defined interfaces are achieved also in the immediate vicinity of the surface, where analytic approaches and numerical models become inaccurate. Assisted by finite-element modeling, the details of our device were designed for use with a specific artificial protein motor, but the key results are general and can be applied to a wide range of biochem. studies in which switching is important.
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Niman, C. S., Zuckermann, M. J., Balaz, M., Tegenfeldt, J. O., Curmi, P. M. G., Forde, N. R., and Linke, H. (2014) Fluidic switching in nanochannels for the control of Inchworm: a synthetic biomolecular motor with a power stroke Nanoscale 6, 15008– 15019 DOI: 10.1039/C4NR04701J
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Fluidic switching in nanochannels for the control of Inchworm: a synthetic biomolecular motor with a power stroke
Niman, Cassandra S.; Zuckermann, Martin J.; Balaz, Martina; Tegenfeldt, Jonas O.; Curmi, Paul M. G.; Forde, Nancy R.; Linke, Heiner
Nanoscale (2014), 6 (24), 15008-15019CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
Synthetic mol. motors typically take nanometer-scale steps through rectification of thermal motion. Here we propose Inchworm, a DNA-based motor that employs a pronounced power stroke to take micrometer-scale steps on a time scale of seconds, and we design, fabricate, and analyze the nanofluidic device needed to operate the motor. Inchworm is a kbp-long, double-stranded DNA confined inside a nanochannel in a stretched configuration. Motor stepping is achieved through externally controlled changes in salt concn. (changing the DNA's extension), coordinated with ligand-gated binding of the DNA's ends to the functionalized nanochannel surface. Brownian dynamics simulations predict that Inchworm's stall force is detd. by its entropic spring const. and is ∼0.1 pN. Operation of the motor requires periodic cycling of four different buffers surrounding the DNA inside a nanochannel, while keeping const. the hydrodynamic load force on the DNA. We present a two-layer fluidic device incorporating 100 nm-radius nanochannels that are connected through a few-nm-wide slit to a microfluidic system used for in situ buffer exchanges, either diffusionally (zero flow) or with controlled hydrodynamic flow. Combining expt. with finite-element modeling, we demonstrate the device's key performance features and exptl. establish achievable Inchworm stepping times of the order of seconds or faster.
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Kuwada, N. J., Blab, G. A., and Linke, H. (2010) A classical Master equation approach to modeling an artificial protein motor Chem. Phys. 375, 479– 485 DOI: 10.1016/j.chemphys.2010.05.009
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Kuwada, N. J., Zuckermann, M. J., Bromley, E. H. C., Sessions, R. B., Curmi, P. M. G., Forde, N. R., Woolfson, D. N., and Linke, H. (2011) Tuning the performance of an artificial protein motor Phys. Rev. E 84, 9 DOI: 10.1103/PhysRevE.84.031922
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Apostolovic, B., Danial, M., and Klok, H. A. (2010) Coiled coils: attractive protein folding motifs for the fabrication of self-assembled, responsive and bioactive materials Chem. Soc. Rev. 39, 3541– 3575 DOI: 10.1039/b914339b
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Coiled coils: Attractive protein folding motifs for the fabrication of self-assembled, responsive and bioactive materials
Apostolovic, Bojana; Danial, Maarten; Klok, Harm-Anton
Chemical Society Reviews (2010), 39 (9), 3541-3575CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
A review. The coiled-coil is a superhelical protein structural motif that consists of 2 or more α-helical peptides that are wrapped around each other in superhelical fashion. Coiled-coils are among the most ubiquitous folding motifs found in proteins and have not only been identified in structural proteins but also play an important role in various intracellular regulation processes as well as membrane fusion. The aim of this crit. review is to highlight the potential of coiled coil peptide sequences for the development of self-assembled, responsive and/or bioactive materials. After a short historical overview outlining the discovery of this protein folding motif, the article briefly discusses naturally occurring coiled-coils. After that, the basic rules, which have been established to date for the design of coiled-coils is briefly summarized followed by a presentation of several classes of coiled-coils, which may represent interesting candidates for the development of novel self-assembled, responsive and/or bioactive materials. This crit. review ends with a section that summarizes the different coiled-coil-based (hybrid) materials that have been reported to date and which hopefully will help to stimulate further work to explore the full potential of this unique class of protein folding motifs for the development of novel self-assembled, responsive and/or bioactive materials.
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Newman, J. R. S. and Keating, A. E. (2003) Comprehensive identification of human bZIP interactions with coiled-coil arrays Science 300, 2097– 2101 DOI: 10.1126/science.1084648
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Comprehensive Identification of Human bZIP Interactions with Coiled-Coil Arrays
Newman, John R. S.; Keating, Amy E.
Science (Washington, DC, United States) (2003), 300 (5628), 2097-2101CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
In eukaryotes, the combinatorial assocn. of sequence-specific DNA binding proteins is essential for transcription. The authors have used protein arrays to test 492 pairings of a nearly complete set of coiled-coil strands from human basic-region leucine zipper (bZIP) transcription factors. The authors find considerable partnering selectivity despite the bZIPs' homologous sequences. The interaction data are of high quality, as assessed by their reproducibility, reciprocity, and agreement with previous observations. Biophys. studies in soln. support the relative binding strengths obsd. with the arrays. New assocns. provide insights into the circadian clock and the unfolded protein response.
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Kaplan, J. B., Reinke, A. W., and Keating, A. E. (2014) Increasing the affinity of selective bZIP-binding peptides through surface residue redesign Protein Sci. 23, 940– 953 DOI: 10.1002/pro.2477
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Increasing the affinity of selective bZIP-binding peptides through surface residue redesign
Kaplan, Jenifer B.; Reinke, Aaron W.; Keating, Amy E.
Protein Science (2014), 23 (7), 940-953CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)
The coiled-coil dimer is a prevalent protein interaction motif that is important for many cellular processes. The basic leucine-zipper (bZIP) transcription factors are one family of proteins for which coiled-coil mediated dimerization is essential for function, and misregulation of bZIPs can lead to disease states including cancer. This makes coiled coils attractive protein-protein interaction targets to disrupt using engineered mols. Previous work designing peptides to compete with native coiled-coil interactions focused primarily on designing the core residues of the interface to achieve affinity and specificity. However, folding studies on the model bZIP GCN4 show that coiled-coil surface residues also contribute to binding affinity. Here we extend a prior study in which peptides were designed to bind tightly and specifically to representative members of each of 20 human bZIP families. These "anti-bZIP" peptides were designed with an emphasis on target-binding specificity, with contributions to design-target specificity and affinity engineered considering only the coiled-coil core residues. High-throughput testing using peptide arrays indicated many successes. We have now measured the binding affinities and specificities of anti-bZIPs that bind to FOS, XBP1, ATF6, and CREBZF in soln. and tested whether redesigning the surface residues can increase design-target affinity. Incorporating residues that favor helix formation into the designs increased binding affinities in all cases, providing low-nanomolar binders of each target. However, changes in surface electrostatic interactions sometimes changed the binding specificity of the designed peptides.
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Vilanova, C., Tanner, K., Dorado-Morales, P., Villaescusa, P., Chugani, D., Frias, A., Segredo, E., Molero, X., Fritschi, M., Morales, L., Ramon, D., Pena, C., Pereto, J., and Porcar, M. (2015) Standards not that standard J. Biol. Eng. 9, 4 DOI: 10.1186/s13036-015-0017-9
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Kwok, R. (2010) FIVE HARD TRUTHS FOR SYNTHETIC BIOLOGY Nature 463, 288– 290 DOI: 10.1038/463288a
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Five hard truths for synthetic biology
Kwok, Roberta
Nature (London, United Kingdom) (2010), 463 (7279), 288-290CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
There is no expanded citation for this reference.
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Mason, J. M. and Arndt, K. M. (2004) Coiled coil domains: Stability, specificity, and biological implications ChemBioChem 5, 170– 176 DOI: 10.1002/cbic.200300781
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Coiled coil domains: stability, specificity, and biological implications
Mason, Jody M.; Arndt, Katja M.
ChemBioChem (2004), 5 (2), 170-176CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review discusses the importance of individual amino acids in maintaining α-helical structure (intramol. interactions) within individual helixes, while promoting specific coiled-coil interactions (intermol. interactions) of correct oligomeric state and orientation.
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Woolfson, D. N. (2005) The design of coiled-coil structures and assemblies Adv. Protein Chem. 70, 79 DOI: 10.1016/S0065-3233(05)70004-8
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The design of coiled-coil structures and assemblies
Woolfson, Derek N.
Advances in Protein Chemistry (2005), 70 (Fibrous Proteins: Coiled-Coils, Collagen and Elastomers), 79-112CODEN: APCHA2; ISSN:0065-3233. (Elsevier)
A review. Protein design allows sequence-to-structure relationships in proteins to be examd. and, potentially, new protein structures and functions to be made to order. To succeed, however, the protein-design process requires reliable rules that link protein sequence to structure/function. Although the present understanding of coiled-coil folding and assembly is not complete, through numerous bioinformatics and exptl. studies there are now sufficient rules to allow confident design attempts of naturally obsd. and even novel coiled-coil motifs. This review summarizes the current design rules for coiled coils, and describes some of the key successful coiled-coil designs that were created to date. The designs range from those for relatively straightforward, naturally obsd. structures-including parallel and antiparallel dimers, trimers and tetramers, all of which were made as homomers and heteromers-to more exotic structures that expand the repertoire of Nature's coiled-coil structures. Examples in the second bracket include a probe that binds a cancer-assocd. coiled-coil protein; a tetramer with a right-handed super-coil; sticky-ended coiled coils that self-assemble to form fibers; coiled coils that switch conformational state; a 3-component 2-stranded coiled coil; and an antiparallel dimer that directs fragment complementation of larger proteins. Some of the more recent examples show an important development in the field; namely, new designs are being created with function as well as structure in mind. This will remain one of the key challenges in coiled-coil design in the next few years. Other challenges that lie ahead include the need to discover more rules for coiled-coil prediction and design, and to implement these in prediction and design algorithms. The considerable success of coiled-coil design so far bodes well for this, however. It is likely that these challenges will be met and surpassed.
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Gradisar, H., Bozic, S., Doles, T., Vengust, D., Hafner-Bratkovic, I., Mertelj, A., Webb, B., Sali, A., Klavzar, S., and Jerala, R. (2013) Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments Nat. Chem. Biol. 9, 362 DOI: 10.1038/nchembio.1248
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Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments
Gradisar, Helena; Bozic, Sabina; Doles, Tibor; Vengust, Damjan; Hafner-Bratkovic, Iva; Mertelj, Alenka; Webb, Ben; Sali, Andrej; Klavzar, Sandi; Jerala, Roman
Nature Chemical Biology (2013), 9 (6), 362-366CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
Protein structures evolved through a complex interplay of cooperative interactions, and it is still very challenging to design new protein folds de novo. Here we present a strategy to design self-assembling polypeptide nanostructured polyhedra based on modularization using orthogonal dimerizing segments. We designed and exptl. demonstrated the formation of the tetrahedron that self-assembles from a single polypeptide chain comprising 12 concatenated coiled coil-forming segments sepd. by flexible peptide hinges. The path of the polypeptide chain is guided by a defined order of segments that traverse each of the six edges of the tetrahedron exactly twice, forming coiled-coil dimers with their corresponding partners. The coincidence of the polypeptide termini in the same vertex is demonstrated by reconstituting a split fluorescent protein in the polypeptide with the correct tetrahedral topol. Polypeptides with a deleted or scrambled segment order fail to self-assemble correctly. This design platform provides a foundation for constructing new topol. polypeptide folds based on the set of orthogonal interacting polypeptide segments.
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Raman, S., Machaidze, G., Lustig, A., Aebi, U., and Burkhard, P. (2006) Structure-based design of peptides that self-assemble into regular polyhedral nanoparticles Nanomedicine 2, 95– 102 DOI: 10.1016/j.nano.2006.04.007
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Structure-based design of peptides that self-assemble into regular polyhedral nanoparticles
Raman, Senthilkumar; Machaidze, Gia; Lustig, Ariel; Aebi, Ueli; Burkhard, Peter
Nanomedicine (2006), 2 (2), 95-102CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
Artificial particulate systems such as polymeric beads and liposomes are being applied in drug delivery, drug targeting, antigen display, vaccination, and other technologies. Here we used computer modeling to design a novel type of nanoparticles composed of peptides as building blocks. We verified the computer models via solid-phase peptide synthesis and biophys. analyses. We describe the structure-based design of a novel type of nanoparticles with regular polyhedral symmetry and a diam. of about 16 nm, which self-assembles from single polypeptide chains. Each peptide chain is composed of two coiled coil oligomerization domains with different oligomerization states joined by a short linker segment. In aq. soln. the peptides form nanoparticles of about 16 nm diam. Such peptide nanoparticles are ideally suited for medical applications such as drug targeting and drug delivery systems, such as imaging devices, or they may be used for repetitive antigen display.
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Burgess, N. C., Sharp, T. H., Thomas, F., Wood, C. W., Thomson, A. R., Zaccai, N. R., Brady, R. L., Serpell, L. C., and Woolfson, D. N. (2015) Modular Design of Self-Assembling Peptide-Based Nanotubes J. Am. Chem. Soc. 137, 10554– 10562 DOI: 10.1021/jacs.5b03973
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Modular Design of Self-Assembling Peptide-Based Nanotubes
Burgess, Natasha C.; Sharp, Thomas H.; Thomas, Franziska; Wood, Christopher W.; Thomson, Andrew R.; Zaccai, Nathan R.; Brady, R. Leo; Serpell, Louise C.; Woolfson, Derek N.
Journal of the American Chemical Society (2015), 137 (33), 10554-10562CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
An ability to design peptide-based nanotubes (PNTs) rationally with defined and mutable internal channels would advance understanding of peptide self-assembly, and present new biomaterials for nanotechnol. and medicine. PNTs have been made from Fmoc dipeptides, cyclic peptides, and lock-washer helical bundles. Here we show that blunt-ended α-helical barrels, i.e., preassembled bundles of α-helixes with central channels, can be used as building blocks for PNTs. This approach is general and systematic, and uses a set of de novo helical bundles as stds. One of these bundles, a hexameric α-helical barrel, assembles into highly ordered PNTs, for which we have detd. a structure by combining cryo-transmission electron microscopy, X-ray fiber diffraction, and model building. The structure reveals that the overall symmetry of the peptide module plays a crit. role in ripening and ordering of the supramol. assembly. PNTs based on pentameric, hexameric, and heptameric α-helical barrels sequester hydrophobic dye within their lumens.
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Fletcher, J. M., Boyle, A. L., Bruning, M., Bartlett, G. J., Vincent, T. L., Zaccai, N. R., Armstrong, C. T., Bromley, E. H. C., Booth, P. J., and Brady, R. L. 2012, A Basis Set of de Novo Coiled-Coil Peptide Oligomers for Rational Protein Design and Synthetic Biology ACS Synth. Biol. 1, 240– 250 DOI: 10.1021/sb300028q
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A Basis Set of de Novo Coiled-Coil Peptide Oligomers for Rational Protein Design and Synthetic Biology
Fletcher, Jordan M.; Boyle, Aimee L.; Bruning, Marc; Bartlett, Gail J.; Vincent, Thomas L.; Zaccai, Nathan R.; Armstrong, Craig T.; Bromley, Elizabeth H. C.; Booth, Paula J.; Brady, R. Leo; Thomson, Andrew R.; Woolfson, Derek N.
ACS Synthetic Biology (2012), 1 (6), 240-250CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
Protein engineering, chem. biol., and synthetic biol. would benefit from toolkits of peptide and protein components that could be exchanged reliably between systems while maintaining their structural and functional integrity. Ideally, such components should be highly defined and predictable in all respects of sequence, structure, stability, interactions, and function. To establish one such toolkit, here we present a basis set of de novo designed α-helical coiled-coil peptides that adopt defined and well-characterized parallel dimeric, trimeric, and tetrameric states. The designs are based on sequence-to-structure relationships both from the literature and anal. of a database of known coiled-coil X-ray crystal structures. These give foreground sequences to specify the targeted oligomer state. A key feature of the design process is that sequence positions outside of these sites are considered non-essential for structural specificity; as such, they are referred to as the background, are kept non-descript, and are available for mutation as required later. Synthetic peptides were characterized in soln. by circular-dichroism spectroscopy and anal. ultracentrifugation, and their structures were detd. by X-ray crystallog. Intriguingly, a hitherto widely used empirical rule-of-thumb for coiled-coil dimer specification does not hold in the designed system. However, the desired oligomeric state is achieved by database-informed redesign of that particular foreground and confirmed exptl. We envisage that the basis set will be of use in directing and controlling protein assembly, with potential applications in chem. and synthetic biol. To help with such endeavors, we introduce Pcomp, an online registry of peptide components for protein-design and synthetic-biol. applications.
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Fletcher, J. M., Harniman, R. L., Barnes, F. R. H., Boyle, A. L., Collins, A., Mantell, J., Sharp, T. H., Antognozzi, M., Booth, P. J., and Linden, N. 2013, Self-Assembling Cages from Coiled-Coil Peptide Modules Science 340, 595– 599 DOI: 10.1126/science.1233936
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Self-Assembling Cages from Coiled-Coil Peptide Modules
Fletcher, Jordan M.; Harniman, Robert L.; Barnes, Frederick R. H.; Boyle, Aimee L.; Collins, Andrew; Mantell, Judith; Sharp, Thomas H.; Antognozzi, Massimo; Booth, Paula J.; Linden, Noah; Miles, Mervyn J.; Sessions, Richard B.; Verkade, Paul; Woolfson, Derek N.
Science (Washington, DC, United States) (2013), 340 (6132), 595-599CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
An ability to mimic the boundaries of biol. compartments would improve our understanding of self-assembly and provide routes to new materials for the delivery of drugs and biologicals and the development of protocells. We show that short designed peptides can be combined to form unilamellar spheres approx. 100 nm in diam. The design comprises two, noncovalent, heterodimeric and homotrimeric coiled-coil bundles. These are joined back to back to render two complementary hubs, which when mixed form hexagonal networks that close to form cages. This design strategy offers control over chem., self-assembly, reversibility, and size of such particles.
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Grigoryan, G. and Keating, A. E. (2006) Structure-based prediction of bZIP partnering specificity J. Mol. Biol. 355, 1125– 1142 DOI: 10.1016/j.jmb.2005.11.036
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Structure-based Prediction of bZIP Partnering Specificity
Grigoryan, Gevorg; Keating, Amy E.
Journal of Molecular Biology (2006), 355 (5), 1125-1142CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)
Predicting protein interaction specificity from sequence is an important goal in computational biol. We present a model for predicting the interaction preferences of coiled-coil peptides derived from bZIP transcription factors that performs very well when tested against exptl. protein microarray data. We used only sequence information to build at.-resoln. structures for 1711 dimeric complexes, and evaluated these with a variety of functions based on physics, learned empirical wts. or exptl. coupling energies. A purely phys. model, similar to those used for protein design studies, gave reasonable performance. The results were improved significantly when helix propensities were used in place of a structurally explicit model to represent the unfolded ref. state. Further improvement resulted upon accounting for residue-residue interactions in competing states in a generic way. Purely phys. structure-based methods had difficulty capturing core interactions accurately, esp. those involving polar residues such as asparagine. When these terms were replaced with wts. from a machine-learning approach, the resulting model was able to correctly order the stabilities of over 6000 pairs of complexes with greater than 90% accuracy. The final model is phys. interpretable, and suggests specific pairs of residues that are important for bZIP interaction specificity. Our results illustrate the power and potential of structural modeling as a method for predicting protein interactions and highlight obstacles that must be overcome to reach quant. accuracy using a de novo approach. Our method shows unprecedented performance in predicting protein-protein interaction specificity accurately using structural modeling and suggests that predicting coiled-coil interactions generally may be within reach.
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Ramisch, S., Lizatovic, R., and Andre, I. (2015) Exploring alternate states and oligomerization preferences of coiled-coils by de novo structure modeling Proteins: Struct., Funct., Genet. 83, 235– 247 DOI: 10.1002/prot.24729
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Thomson, A. R., Wood, C. W., Burton, A. J., Bartlett, G. J., Sessions, R. B., Brady, R. L., and Woolfson, D. N. (2014) Computational design of water-soluble alpha-helical barrels Science 346, 485– 488 DOI: 10.1126/science.1257452
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Computational design of water-soluble α-helical barrels
Thomson, Andrew R.; Wood, Christopher W.; Burton, Antony J.; Bartlett, Gail J.; Sessions, Richard B.; Brady, R. Leo; Woolfson, Derek N.
Science (Washington, DC, United States) (2014), 346 (6208), 485-488CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
The design of protein sequences that fold into prescribed de novo structures is challenging. General solns. to this problem require geometric descriptions of protein folds and methods to fit sequences to these. The α-helical coiled coils present a promising class of protein for this and offer considerable scope for exploring hitherto unseen structures. For α-helical barrels, which have more than four helixes and accessible central channels, many of the possible structures remain unobserved. Here, we combine geometrical considerations, knowledge-based scoring, and atomistic modeling to facilitate the design of new channel-contg. α-helical barrels. X-ray crystal structures of the resulting designs match predicted in silico models. Furthermore, the obsd. channels are chem. defined and have diams. related to oligomer state, which present routes to design protein function.
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Boyle, A. L., Bromley, E. H. C., Bartlett, G. J., Sessions, R. B., Sharp, T. H., Williams, C. L., Curmi, P. M. G., Forde, N. R., Linke, H., and Woolfson, D. N. (2012) Squaring the Circle in Peptide Assembly: From Fibers to Discrete Nanostructures by de Novo Design J. Am. Chem. Soc. 134, 15457– 15467 DOI: 10.1021/ja3053943
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Squaring the Circle in Peptide Assembly: From Fibers to Discrete Nanostructures by de Novo Design
Boyle, Aimee L.; Bromley, Elizabeth H. C.; Bartlett, Gail J.; Sessions, Richard B.; Sharp, Thomas H.; Williams, Claire L.; Curmi, Paul M. G.; Forde, Nancy R.; Linke, Heiner; Woolfson, Derek N.
Journal of the American Chemical Society (2012), 134 (37), 15457-15467CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
The design of bioinspired nanostructures and materials of defined size and shape is challenging as it pushes the authors' understanding of biomol. assembly to its limits. In such endeavors, DNA is the current building block of choice because of its predictable and programmable self-assembly. The use of peptide- and protein-based systems, however, has potential advantages due to their more-varied chemistries, structures and functions, and the prospects for recombinant prodn. through gene synthesis and expression. Here, the authors present the design and characterization of two complementary peptides programmed to form a parallel heterodimeric coiled coil, which the authors use as the building blocks for larger, supramol. assemblies. To achieve the latter, the two peptides are joined via peptidic linkers of variable lengths to produce a range of assemblies, from flexible fibers of indefinite length, through large colloidal-scale assemblies, down to closed and discrete nanoscale objects of defined stoichiometry. The authors posit that the different modes of assembly reflect the interplay between steric constraints imposed by short linkers and the bulk of the helixes, and entropic factors that favor the formation of many smaller objects as the linker length is increased. This approach, and the resulting linear and proteinogenic polypeptides, represents a new route for constructing complex peptide-based assemblies and biomaterials.
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Chen, X. Y., Zaro, J. L., and Shen, W. C. (2013) Fusion protein linkers: Property, design and functionality Adv. Drug Delivery Rev. 65, 1357– 1369 DOI: 10.1016/j.addr.2012.09.039
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Fusion protein linkers: Property, design and functionality
Chen, Xiaoying; Zaro, Jennica L.; Shen, Wei-Chiang
Advanced Drug Delivery Reviews (2013), 65 (10), 1357-1369CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
A review. As an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in the construction of stable, bioactive fusion proteins. This review covers the current knowledge of fusion protein linkers and summarizes examples for their design and application. The general properties of linkers derived from naturally-occurring multi-domain proteins can be considered as the foundation in linker design. Empirical linkers designed by researchers are generally classified into 3 categories according to their structures: flexible linkers, rigid linkers, and in vivo cleavable linkers. Besides the basic role in linking the functional domains together (as in flexible and rigid linkers) or releasing the free functional domain in vivo (as in in vivo cleavable linkers), linkers may offer many other advantages for the prodn. of fusion proteins, such as improving biol. activity, increasing expression yield, and achieving desirable pharmacokinetic profiles.
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Bromley, E. H. C., Sessions, R. B., Thomson, A. R., and Woolfson, D. N. (2009) Designed alpha-Helical Tectons for Constructing Multicomponent Synthetic Biological Systems J. Am. Chem. Soc. 131, 928– 930 DOI: 10.1021/ja804231a
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There is no corresponding record for this reference.
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Cerpa, R., Cohen, F. E., and Kuntz, I. D. (1996) Conformational switching in designed peptides: The helix/sheet transition Folding Des. 1, 91– 101 DOI: 10.1016/S1359-0278(96)00018-1
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Conformational switching in designed peptides: the helix/sheet transition
Cerpa, Robert; Cohen, Fred E.; Kuntz, Irwin D.
Folding & Design (1996), 1 (2), 91-101CODEN: FODEFH; ISSN:1359-0278. (Current Biology)
The structure adopted by peptides and proteins depends not only on the primary sequence, but also on conditions such as solvent polarity or method of sample prepn. We examd. the effect that soln. conditions have on the folded conformations of two peptides, one of which contains the photoisomerizable amino acid p-phenylazo-L-phenylalanine. Spectroscopic studies indicate that these two peptides switch between helical and β sheet conformations. The switch behavior is influenced by soln. conditions including pH, NaCl concn., temp., and peptide concn. The CD spectrum of the peptide contg. p-phenylazo-L-phenylalanine changes from a spectrum characteristic of a β sheet to one characteristic of an α helix upon irradn. We hypothesize that the structural states of the peptides are a monomeric α helix and an aggregated antiparallel β sheet. Conditions encouraging aggregation tend to favor sheet; conditions discouraging aggregation tend to favor helix. Consideration of such soln.-dependent conformational changes may affect de novo protein design and have a bearing on certain biol. processes.
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Webber, M. J., Newcomb, C. J., Bitton, R., and Stupp, S. I. (2011) Switching of self-assembly in a peptide nanostructure with a specific enzyme Soft Matter 7, 9665– 9672 DOI: 10.1039/c1sm05610g
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Switching of self-assembly in a peptide nanostructure with a specific enzyme
Webber, Matthew J.; Newcomb, Christina J.; Bitton, Ronit; Stupp, Samuel I.
Soft Matter (2011), 7 (20), 9665-9672CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
Peptide self-assembly has been shown to be a useful tool for the prepn. of bioactive nanostructures, and recent work has demonstrated their potential as therapies for regenerative medicine. In principle, one route to make these nanostructures more biomimetic would be to incorporate in their mol. design the capacity for biol. sensing. We report here on the use of a reversible enzymic trigger to control the assembly and disassembly of peptide amphiphile (PA) nanostructures. The PA used in these studies contained a consensus substrate sequence specific to protein kinase A (PKA), a biol. enzyme important for intracellular signaling that has also been shown to be an extracellular cancer biomarker. Upon treatment with PKA, this PA mol. becomes phosphorylated causing the high aspect-ratio filamentous PA nanostructures to disassemble. Treatment with an enzyme to cleave the phosphate group results in reformation of the filamentous nanostructures. We also show that disassembly in the presence of PKA allows the enzyme-triggered release of an encapsulated cancer drug. In addn., these drug-loaded nanostructures were found to induce preferential cytotoxicity in a cancer cell line that is known to secrete high levels of PKA. This ability to control nanostructure through an enzymic switch could allow for the prepn. of highly sophisticated and biomimetic materials that incorporate a biol. sensing capability to enable therapeutic specificity.
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Zimenkov, Y., Dublin, S. N., Ni, R., Tu, R. S., Breedveld, V., Apkarian, R. P., and Conticello, V. P. (2006) Rational design of a reversible pH-responsive switch for peptide self-assembly J. Am. Chem. Soc. 128, 6770– 6771 DOI: 10.1021/ja0605974
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Rational design of a reversible pH-responsive switch for peptide self-assembly
Zimenkov, Yuri; Dublin, Steven N.; Ni, Rong; Tu, Raymond S.; Breedveld, Victor; Apkarian, Robert P.; Conticello, Vincent P.
Journal of the American Chemical Society (2006), 128 (21), 6770-6771CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
Peptide TZ1H, based on the heptad sequence of a coiled-coil trimer, undergoes fully reversible, pH-dependent self-assembly into long-aspect-ratio helical fibers. Substitution of isoleucine residues with histidine at the core d-positions of alternate heptads introduces a mechanism by which self-assembly is coupled to the protonation state of the imidazole side chain. CD spectroscopy, transmission electron microscopy, and microrheol. techniques revealed that the self-assembly of TZ1H coincides with a distinct coil-helix conformational transition that occurs within a narrow pH range near the pKa of the imidazole side chains of the core histidine residues.
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Abstract
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Figure 1
Figure 1. “Y” configuration of the Tumbleweed Hub. The peptide hub termini are indicated, showing the parallel coiled coils p1,p2 and p3,p4, and the antiparallel coiled coil p5,p6. To form a hub, coiled-coil pairs (p1,p2), (p3,p4), and (p5,p6) need to preferentially interact, while p1 and p6, p2 and p3, and p4 and p5 are covalently linked, to ensure that all of the coiled coils are connected to form one structure. The nonhelical central ribbons represent the residues at one end of every peptide that are designed not to contribute to a coiled-coil region. Figure adapted with permission from ref 22. Copyright 2011 American Physical Society.
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Figure 2
Figure 2. CD spectra of the three mixtures of the designed pairs of peptides: (a) p1 and p2, (b) p3 and p4, and (c) p5 and p6 (shown in green). Each panel also shows the individual peptide spectra (red and blue, in numerical order), and the theoretical signal for a mixture of the two without interaction (a combination of the two single peptide signals, shown in purple). (d) CD spectrum of all six hub peptides mixed together (green), compared with the theoretical spectrum predicted from the individual spectra (shown in magenta), and from the designed pair spectra (shown in purple). Each sample had a concentration of 20 μM per peptide, in PBS buffer (pH 7.4), measured at 20 °C. Dotted lines represent the wavelength cutoff below which data cannot be reliably obtained, as dictated by the CD instrument.
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Figure 3
Figure 3. If the designed dimer peptides preferentially interact, when allowed to rearrange, the disulfide bonds should switch to being between the desired pairs, with the species present in the system moving from p6–p1, p3–p2, and p4–p5 to p1–p2, p3–p4, and p5–p6.
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Figure 4
Figure 4. MALDI spectra of glutathione experiments. The initial spectrum has prominent peaks due to the p4–p5 (MW 6682 Da) and p3–p2 (MW 7095 Da) species, and smaller peaks due to deletions and the p6–p1 peptide (MW 6470 Da). After rearrangement, the p4–p5 and p6–p1 species are no longer seen, while the p6–p5 (MW 5814 Da), p1–p2 (MW 7039 Da) and p3–p4 (MW 7395 Da) species have appeared. All of the trace peaks correlate with impurities in the initial samples and do not correlate with possible rearrangements.
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References
This article references 43 other publications.
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  A review. Eukaryotic cells create internal order by using protein motors to transport mols. and organelles along cytoskeletal tracks. Recent genomic and functional studies suggest that 5 cargo-carrying motors emerged in primitive eukaryotes and have been widely used throughout evolution. The complexity of these "toolbox" motors expanded in higher eukaryotes through gene duplication, alternative splicing, and the addn. of assocd. subunits, which enabled new cargoes to be transported. Remarkably, fungi, parasites, plants, and animals have distinct subsets of toolbox motors in their genomes, suggesting an underlying diversity of strategies for intracellular transport.
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  A review. The biol. cell is equipped with a variety of mol. machines that perform complex mech. tasks such as cell division or intracellular transport. One can envision employing these biol. motors in artificial environments. The authors review the progress that has been made in using motor proteins for powering or manipulating nanoscale components. In particular, kinesin and myosin biomotors that move along linear biofilaments have been widely explored as active components. Currently realized applications are merely proof-of-principle demonstrations. Yet, the sheer availability of an entire ready-to-use toolbox of nanosized biol. motors is a great opportunity that calls for exploration.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD2sXnslGrs7Y%253D&md5=96877d4426278f133b82783e7e0ac9c7
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  Peptide and Protein Building Blocks for Synthetic Biology: From Programming Biomolecules to Self-Organized Biomolecular Systems
  Bromley, Elizabeth H. C.; Channon, Kevin; Moutevelis, Efrosini; Woolfson, Derek N.
  ACS Chemical Biology (2008), 3 (1), 38-50CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
  A review. There are several approaches to creating synthetic-biol. systems. Here, the authors describe a mol.-design approach. First, the authors lay out a possible synthetic-biol. space, which the authors define with a plot of complexity of components vs. divergence from nature. In this scheme, there are basic units, which range from natural amino acids to totally synthetic small mols. These are linked together to form programmable tectons, for example, amphipathic α-helixes. In turn, tectons can interact to give self-assembled units, which can combine and organize further to produce functional assemblies and systems. To illustrate one path through this vast landscape, the authors focus on protein engineering and design. The authors describe how, for certain protein-folding motifs, polypeptide chains can be instructed to fold. These folds can be combined to give structured complexes, and function can be incorporated through computational design. Finally, the authors describe how protein-based systems may be encapsulated to control and investigate their functions.
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  6
  Synthetic biology through biomolecular design and engineering
  Channon, Kevin; Bromley, Elizabeth H. C.; Woolfson, Derek N.
  Current Opinion in Structural Biology (2008), 18 (4), 491-498CODEN: COSBEF; ISSN:0959-440X. (Elsevier B.V.)
  A review. Synthetic biol. is a rapidly growing field that has emerged in a global, multidisciplinary effort among biologists, chemists, engineers, physicists, and mathematicians. Broadly, the field has 2 complementary goals: (1) to improve understanding of biol. systems through mimicry and (2) to produce bio-orthogonal systems with new functions. Here, the authors review the area specifically with ref. to the concept of synthetic biol. space, i.e., a hierarchy of components for, and approaches to generating new synthetic and functional systems to test, advance, and apply the understanding of biol. systems. Here, the authors focus largely on the design and engineering of biomol.-based components and systems.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXhtValt7%252FF&md5=720694e46a99cccee8c6d8f955cab6f3
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  7
  Artificial Molecular Machines
  Erbas-Cakmak, Sundus; Leigh, David A.; McTernan, Charlie T.; Nussbaumer, Alina L.
  Chemical Reviews (Washington, DC, United States) (2015), 115 (18), 10081-10206CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
  This paper reviews triggered large-amplitude motions in mol. structures and the changes in properties these can produce. The focus is on conformational and configurational changes in wholly covalently bonded mols. and on catenanes and rotaxanes in which switching is brought about by various stimuli. Also discussed is the latest generations of sophisticated synthetic mol. machine systems in which the controlled motion of subcomponents is used to perform complex tasks, paving the way to applications and the realization of a new era of "mol. nanotechnol.".
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8. 8
  Kassem, S., Lee, A. T. L., Leigh, D. A., Markevicius, A., and Sola, J. (2016) Pick-up, transport and release of a molecular cargo using a small-molecule robotic arm Nat. Chem. 8, 138– 143 DOI: 10.1038/nchem.2410
  8
  Pick-up, transport and release of a molecular cargo using a small-molecule robotic arm
  Kassem, Salma; Lee, Alan T. L.; Leigh, David A.; Markevicius, Augustinas; Sola, Jordi
  Nature Chemistry (2016), 8 (2), 138-143CODEN: NCAHBB; ISSN:1755-4330. (Nature Publishing Group)
  Modern-day factory assembly lines often feature robots that pick up, reposition and connect components in a programmed manner. The idea of manipulating mol. fragments in a similar way has to date only been explored using biol. building blocks (specifically DNA). Here, we report on a wholly artificial small-mol. robotic arm capable of selectively transporting a mol. cargo in either direction between two spatially distinct, chem. similar, sites on a mol. platform. The arm picks up/releases a 3-mercaptopropanehydrazide cargo by formation/breakage of a disulfide bond, while dynamic hydrazone chem. controls the cargo binding to the platform. Transport is controlled by selectively inducing conformational and configurational changes within an embedded hydrazone rotary switch that steers the robotic arm. In a three-stage operation, 79-85% of 3-mercaptopropanehydrazide mols. are transported in either (chosen) direction between the two platform sites, without the cargo at any time fully dissocg. from the machine nor exchanging with other mols. in the bulk.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2MXitVygur3M&md5=3008b0f0289a6895dc8790d16bd5f75f
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  Chen, Y. J., Groves, B., Muscat, R. A., and Seelig, G. (2015) DNA nanotechnology from the test tube to the cell Nat. Nanotechnol. 10, 748– 760 DOI: 10.1038/nnano.2015.195
  9
  DNA nanotechnology from the test tube to the cell
  Chen, Yuan-Jyue; Groves, Benjamin; Muscat, Richard A.; Seelig, Georg
  Nature Nanotechnology (2015), 10 (9), 748-760CODEN: NNAABX; ISSN:1748-3387. (Nature Publishing Group)
  A review. The programmability of Watson-Crick base pairing, combined with a decrease in the cost of synthesis, has made DNA a widely used material for the assembly of mol. structures and dynamic mol. devices. Working in cell-free settings, researchers in DNA nanotechnol. have been able to scale up system complexity and quant. characterize reaction mechanisms to an extent that is infeasible for engineered gene circuits or other cell-based technologies. However, the most intriguing applications of DNA nanotechnol. - applications that best take advantage of the small size, biocompatibility and programmability of DNA-based systems - lie at the interface with biol. Here, we review recent progress in the transition of DNA nanotechnol. from the test tube to the cell. We highlight key successes in the development of DNA-based imaging probes, prototypes of smart therapeutics and drug delivery systems, and explore the future challenges and opportunities for cellular DNA nanotechnol.
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10. 10
  Pan, J., Li, F. R., Cha, T. G., Chen, H. R., and Choi, J. H. (2015) Recent progress on DNA based walkers Curr. Opin. Biotechnol. 34, 56– 64 DOI: 10.1016/j.copbio.2014.11.017
  10
  Recent progress on DNA based walkers
  Pan, Jing; Li, Feiran; Cha, Tae-Gon; Chen, Haorong; Choi, Jong Hyun
  Current Opinion in Biotechnology (2015), 34 (), 56-64CODEN: CUOBE3; ISSN:0958-1669. (Elsevier B.V.)
  A review. DNA based synthetic mol. walkers are reminiscent of biol. protein motors. They are powered by hybridization with fuel strands, environment induced conformational transitions, and covalent chem. of oligonucleotides. Recent developments in exptl. techniques enable direct observation of individual walkers with high temporal and spatial resoln. The functionalities of state-of-the-art DNA walker systems can thus be analyzed for various applications. Herein we review recent progress on DNA walker principles and characterization methods, and evaluate various aspects of their functions for future applications.
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  https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXitVWktbfK&md5=cf4f5c3ae20d3421310e005b41576fa8
11. 11
  Lund, K., Manzo, A. J., Dabby, N., Michelotti, N., Johnson-Buck, A., Nangreave, J., Taylor, S., Pei, R. J., Stojanovic, M. N., and Walter, N. G. 2010, Molecular robots guided by prescriptive landscapes Nature 465, 206– 210 DOI: 10.1038/nature09012
  11
  Molecular robots guided by prescriptive landscapes
  Lund, Kyle; Manzo, Anthony J.; Dabby, Nadine; Michelotti, Nicole; Johnson-Buck, Alexander; Nangreave, Jeanette; Taylor, Steven; Pei, Renjun; Stojanovic, Milan N.; Walter, Nils G.; Winfree, Erik; Yan, Hao
  Nature (London, United Kingdom) (2010), 465 (7295), 206-210CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  Traditional robots rely for their function on computing, to store internal representations of their goals and environment and to coordinate sensing and any actuation of components required in response. Moving robotics to the single-mol. level is possible in principle, but requires facing the limited ability of individual mols. to store complex information and programs. One strategy to overcome this problem is to use systems that can obtain complex behavior from the interaction of simple robots with their environment. A first step in this direction was the development of DNA walkers, which have developed from being non-autonomous to being capable of directed but brief motion on one-dimensional tracks. Here we demonstrate that previously developed random walkers--so-called mol. spiders that comprise a streptavidin mol. as an inert 'body' and three deoxyribozymes as catalytic 'legs'--show elementary robotic behavior when interacting with a precisely defined environment. Single-mol. microscopy observations confirm that such walkers achieve directional movement by sensing and modifying tracks of substrate mols. laid out on a two-dimensional DNA origami landscape. When using appropriately designed DNA origami, the mol. spiders autonomously carry out sequences of actions such as 'start', 'follow', 'turn' and 'stop'. We anticipate that this strategy will result in more complex robotic behavior at the mol. level if addnl. control mechanisms are incorporated. One example might be interactions between multiple mol. robots leading to collective behavior; another might be the ability to read and transform secondary cues on the DNA origami landscape as a means of implementing Turing-universal algorithmic behavior.
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12. 12
  Ikezoe, Y., Fang, J., Wasik, T. L., Shi, M. L., Uemura, T., Kitagawa, S., and Matsui, H. (2015) Peptide-Metal Organic Framework Swimmers that Direct the Motion toward Chemical Targets Nano Lett. 15, 4019– 4023 DOI: 10.1021/acs.nanolett.5b00969
  12
  Peptide-Metal Organic Framework Swimmers that Direct the Motion toward Chemical Targets
  Ikezoe, Yasuhiro; Fang, Justin; Wasik, Tomasz L.; Shi, Menglu; Uemura, Takashi; Kitagawa, Susumu; Matsui, Hiroshi
  Nano Letters (2015), 15 (6), 4019-4023CODEN: NALEFD; ISSN:1530-6984. (American Chemical Society)
  Highly efficient and robust chem. motors are expected for the application in microbots that can selectively swim toward targets and accomplish their tasks in sensing, labeling, and delivering. However, one of major issues for such development is that current artificial swimmers have difficulty controlling their directional motion toward targets like bacterial chemotaxis. To program synthetic motors with sensing capability for the target-directed motion, we need to develop swimmers whose motions are sensitive to chem. gradients in environments. Here we create a new intelligent biochem. swimmer by integrating metal org. frameworks (MOFs) and peptides that can sense toxic heavy metals in soln. and swim toward the targets. With the aid of Pb-binding enzymes, the peptide-MOF motor can directionally swim toward PbSe quantum dots (QD) by sensing pH gradient and eventually complete the motion as the swimmer reaches the highest gradient point at the target position in soln. This type of technol. could be evolved to miniaturize chem. robotic systems that sense target chems. and swim toward target locations.
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13. 13
  Ikezoe, Y., Washino, G., Uemura, T., Kitagawa, S., and Matsui, H. (2012) Autonomous motors of a metal-organic framework powered by reorganization of self-assembled peptides at interfaces Nat. Mater. 11, 1081– 1085 DOI: 10.1038/nmat3461
  13
  Autonomous motors of a metal-organic framework powered by reorganization of self-assembled peptides at interfaces
  Ikezoe, Yasuhiro; Washino, Gosuke; Uemura, Takashi; Kitagawa, Susumu; Matsui, Hiroshi
  Nature Materials (2012), 11 (12), 1081-1085CODEN: NMAACR; ISSN:1476-1122. (Nature Publishing Group)
  A variety of microsystems have been developed that harness energy and convert it to mech. motion. Here we have developed new autonomous biochem. motors by integrating a metal-org. framework (MOF) and self-assembling peptides. The MOF is applied as an energy-storing cell that assembles peptides inside nanoscale pores of the coordination framework. The nature of peptides enables their assemblies to be reconfigured at the water/MOF interface, and thus converted to fuel energy. Reorganization of hydrophobic peptides can create a large surface-tension gradient around the MOF that can efficiently power its translational motion. As a comparison, the velocity normalized by vol. for the diphenylalanine-MOF particle is faster and the kinetic energy per unit mass of fuel is more than twice as great as that for previous gel motor systems. This demonstration opens the route towards new applications of MOFs and reconfigurable mol. self-assembly, possibly evolving into a smart autonomous motor capable of mimicking swimming bacteria, and with integrated recognition units, harvesting target chems.
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14. 14
  Nagatsugi, F., Takahashi, Y., Kobayashi, M., Kuwahara, S., Kusano, S., Chikuni, T., Hagihara, S., and Harada, N. (2013) Synthesis of peptide-conjugated light-driven molecular motors and evaluation of their DNA-binding properties Mol. BioSyst. 9, 969– 973 DOI: 10.1039/c2mb25520k
  14
  Synthesis of peptide-conjugated light-driven molecular motors and evaluation of their DNA-binding properties
  Nagatsugi, Fumi; Takahashi, Yusuke; Kobayashi, Maiko; Kuwahara, Shunsuke; Kusano, Shuhei; Chikuni, Tomoko; Hagihara, Shinya; Harada, Nobuyuki
  Molecular BioSystems (2013), 9 (5), 969-973CODEN: MBOIBW; ISSN:1742-2051. (Royal Society of Chemistry)
  Synthetic light-driven mol. motors are mol. machines capable of rotation under photo-irradn. In this paper, the authors report the synthesis of peptide-conjugated mol. motors and evaluate their DNA-binding properties.
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15. 15
  Watson, M. A. and Cockroft, S. L. (2016) Man-made molecular machines: membrane bound Chem. Soc. Rev. 45, 6118 DOI: 10.1039/C5CS00874C
  15
  Man-made molecular machines: membrane bound
  Watson, Matthew A.; Cockroft, Scott L.
  Chemical Society Reviews (2016), 45 (22), 6118-6129CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  Nature's mol. machines are a const. source of inspiration to the chemist. Many of these mol. machines function within lipid membranes, allowing them to exploit potential gradients between spatially close, but chem. distinct environments to fuel their work cycle. Indeed, the realization of such principles in synthetic transmembrane systems remains a tantalising goal. This tutorial review opens by highlighting seminal examples of synthetic mol. machines. We illustrate the importance of surfaces for facilitating the extn. of work from mol. switches and motors. We chart the development of man-made transmembrane systems; from passive to machine-like stimuli-responsive channels, to fully autonomous transmembrane mol. machines. Finally, we highlight higher-order compartmentalised systems that exhibit emergent properties. We suggest that such higher-order architectures could serve as platforms for sophisticated devices that coordinate the activity of numerous transmembrane mol. machines.
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16. 16
  Bromley, E. H. C., Kuwada, N. J., Zuckermann, M. J., Donadini, R., Samii, L., Blab, G. A., Gemmen, G. J., Lopez, B. J., Curmi, P. M. G., and Forde, N. R. 2009, The Tumbleweed: towards a synthetic protein motor HFSP J. 3, 204– 212 DOI: 10.2976/1.3111282
  16
  The Tumbleweed: toward a synthetic protein motor
  Bromley, Elizabeth H. C.; Kuwada, Nathan J.; Zuckermann, Martin J.; Donadini, Roberta; Samii, Laleh; Blab, Gerhard A.; Gemmen, Gregory J.; Lopez, Benjamin J.; Curmi, Paul M. G.; Forde, Nancy R.; Woolfson, Derek N.; Linke, Heiner
  HFSP Journal (2009), 3 (3), 204-212CODEN: HJFOA5; ISSN:1955-2068. (HFSP Publishing)
  A review. Biomol. motors have inspired the design and construction of artificial nanoscale motors and machines based on nucleic acids, small mols., and inorg. nanostructures. However, the high degree of sophistication and efficiency of biomol. motors, as well as their specific biol. function, derives from the complexity afforded by protein building blocks. Here, we discuss a novel bottom-up approach to understanding biol. motors by considering the construction of synthetic protein motors. Specifically, we present a design for a synthetic protein motor that moves along a linear track, dubbed the "Tumbleweed.". This concept uses three discrete ligand-dependent DNA-binding domains to perform cyclically ligand-gated, rectified diffusion along a synthesized DNA mol. Here we describe how de novo peptide design and mol. biol. could be used to produce the Tumbleweed, and we explore the fundamental motor operation of such a design using numerical simulations. The construction of this and more sophisticated protein motors is an exciting challenge that is likely to enhance our understanding of the structure-function relationship in biol. motors.
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17. 17
  Zuckermann, M. J., Angstmann, C. N., Schmitt, R., Blab, G. A., Bromley, E. H. C., Forde, N. R., Linke, H., and Curmi, P. M. G. (2015) Motor properties from persistence: a linear molecular walker lacking spatial and temporal asymmetry New J. Phys. 17, 13 DOI: 10.1088/1367-2630/17/5/055017
  There is no corresponding record for this reference.
18. 18
  Kovacic, S., Samii, L., Woolfson, D. N., Curmi, P. M. G., Linke, H., Forde, N. R., and Blab, G. A. (2012) Design and Construction of a One- Dimensional DNA Track for an Artificial Molecular Motor J. Nanomater. 2012, 10 DOI: 10.1155/2012/109238
  There is no corresponding record for this reference.
19. 19
  Niman, C. S., Beech, J. P., Tegenfeldt, J. O., Curmi, P. M. G., Woolfson, D. N., Forde, N. R., and Linke, H. (2013) Controlled microfluidic switching in arbitrary time-sequences with low drag Lab Chip 13, 2389– 2396 DOI: 10.1039/c3lc50194a
  19
  Controlled microfluidic switching in arbitrary time-sequences with low drag
  Niman, Cassandra S.; Beech, Jason P.; Tegenfeldt, Jonas O.; Curmi, Paul M. G.; Woolfson, Derek N.; Forde, Nancy R.; Linke, Heiner
  Lab on a Chip (2013), 13 (12), 2389-2396CODEN: LCAHAM; ISSN:1473-0189. (Royal Society of Chemistry)
  The ability to test the response of cells and proteins to a changing biochem. environment is of interest for studies of fundamental cell physiol. and mol. interactions. In a common exptl. scheme the cells or mols. of interest are attached to a surface and the compn. of the surrounding fluid is changed. It is desirable to be able to switch several different biochem. reagents in any arbitrary order, and to keep the flow velocity low enough so that the cells and mols. remain attached and can be expected to retain their function. Here we develop a device with these capabilities, using U-shaped access channels. We use total-internal reflection fluorescence microscopy to characterize the time-dependent change in concn. during switching of solns. near the device surface. Well-defined fluid interfaces are formed in the immediate vicinity of the surface ensuring distinct switching events. We show that the exptl. data agrees well with Taylor-Aris theory in its range of validity. In addn., we find that well-defined interfaces are achieved also in the immediate vicinity of the surface, where analytic approaches and numerical models become inaccurate. Assisted by finite-element modeling, the details of our device were designed for use with a specific artificial protein motor, but the key results are general and can be applied to a wide range of biochem. studies in which switching is important.
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20. 20
  Niman, C. S., Zuckermann, M. J., Balaz, M., Tegenfeldt, J. O., Curmi, P. M. G., Forde, N. R., and Linke, H. (2014) Fluidic switching in nanochannels for the control of Inchworm: a synthetic biomolecular motor with a power stroke Nanoscale 6, 15008– 15019 DOI: 10.1039/C4NR04701J
  20
  Fluidic switching in nanochannels for the control of Inchworm: a synthetic biomolecular motor with a power stroke
  Niman, Cassandra S.; Zuckermann, Martin J.; Balaz, Martina; Tegenfeldt, Jonas O.; Curmi, Paul M. G.; Forde, Nancy R.; Linke, Heiner
  Nanoscale (2014), 6 (24), 15008-15019CODEN: NANOHL; ISSN:2040-3372. (Royal Society of Chemistry)
  Synthetic mol. motors typically take nanometer-scale steps through rectification of thermal motion. Here we propose Inchworm, a DNA-based motor that employs a pronounced power stroke to take micrometer-scale steps on a time scale of seconds, and we design, fabricate, and analyze the nanofluidic device needed to operate the motor. Inchworm is a kbp-long, double-stranded DNA confined inside a nanochannel in a stretched configuration. Motor stepping is achieved through externally controlled changes in salt concn. (changing the DNA's extension), coordinated with ligand-gated binding of the DNA's ends to the functionalized nanochannel surface. Brownian dynamics simulations predict that Inchworm's stall force is detd. by its entropic spring const. and is ∼0.1 pN. Operation of the motor requires periodic cycling of four different buffers surrounding the DNA inside a nanochannel, while keeping const. the hydrodynamic load force on the DNA. We present a two-layer fluidic device incorporating 100 nm-radius nanochannels that are connected through a few-nm-wide slit to a microfluidic system used for in situ buffer exchanges, either diffusionally (zero flow) or with controlled hydrodynamic flow. Combining expt. with finite-element modeling, we demonstrate the device's key performance features and exptl. establish achievable Inchworm stepping times of the order of seconds or faster.
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21. 21
  Kuwada, N. J., Blab, G. A., and Linke, H. (2010) A classical Master equation approach to modeling an artificial protein motor Chem. Phys. 375, 479– 485 DOI: 10.1016/j.chemphys.2010.05.009
  There is no corresponding record for this reference.
22. 22
  Kuwada, N. J., Zuckermann, M. J., Bromley, E. H. C., Sessions, R. B., Curmi, P. M. G., Forde, N. R., Woolfson, D. N., and Linke, H. (2011) Tuning the performance of an artificial protein motor Phys. Rev. E 84, 9 DOI: 10.1103/PhysRevE.84.031922
  There is no corresponding record for this reference.
23. 23
  Apostolovic, B., Danial, M., and Klok, H. A. (2010) Coiled coils: attractive protein folding motifs for the fabrication of self-assembled, responsive and bioactive materials Chem. Soc. Rev. 39, 3541– 3575 DOI: 10.1039/b914339b
  23
  Coiled coils: Attractive protein folding motifs for the fabrication of self-assembled, responsive and bioactive materials
  Apostolovic, Bojana; Danial, Maarten; Klok, Harm-Anton
  Chemical Society Reviews (2010), 39 (9), 3541-3575CODEN: CSRVBR; ISSN:0306-0012. (Royal Society of Chemistry)
  A review. The coiled-coil is a superhelical protein structural motif that consists of 2 or more α-helical peptides that are wrapped around each other in superhelical fashion. Coiled-coils are among the most ubiquitous folding motifs found in proteins and have not only been identified in structural proteins but also play an important role in various intracellular regulation processes as well as membrane fusion. The aim of this crit. review is to highlight the potential of coiled coil peptide sequences for the development of self-assembled, responsive and/or bioactive materials. After a short historical overview outlining the discovery of this protein folding motif, the article briefly discusses naturally occurring coiled-coils. After that, the basic rules, which have been established to date for the design of coiled-coils is briefly summarized followed by a presentation of several classes of coiled-coils, which may represent interesting candidates for the development of novel self-assembled, responsive and/or bioactive materials. This crit. review ends with a section that summarizes the different coiled-coil-based (hybrid) materials that have been reported to date and which hopefully will help to stimulate further work to explore the full potential of this unique class of protein folding motifs for the development of novel self-assembled, responsive and/or bioactive materials.
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24. 24
  Newman, J. R. S. and Keating, A. E. (2003) Comprehensive identification of human bZIP interactions with coiled-coil arrays Science 300, 2097– 2101 DOI: 10.1126/science.1084648
  24
  Comprehensive Identification of Human bZIP Interactions with Coiled-Coil Arrays
  Newman, John R. S.; Keating, Amy E.
  Science (Washington, DC, United States) (2003), 300 (5628), 2097-2101CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  In eukaryotes, the combinatorial assocn. of sequence-specific DNA binding proteins is essential for transcription. The authors have used protein arrays to test 492 pairings of a nearly complete set of coiled-coil strands from human basic-region leucine zipper (bZIP) transcription factors. The authors find considerable partnering selectivity despite the bZIPs' homologous sequences. The interaction data are of high quality, as assessed by their reproducibility, reciprocity, and agreement with previous observations. Biophys. studies in soln. support the relative binding strengths obsd. with the arrays. New assocns. provide insights into the circadian clock and the unfolded protein response.
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25. 25
  Kaplan, J. B., Reinke, A. W., and Keating, A. E. (2014) Increasing the affinity of selective bZIP-binding peptides through surface residue redesign Protein Sci. 23, 940– 953 DOI: 10.1002/pro.2477
  25
  Increasing the affinity of selective bZIP-binding peptides through surface residue redesign
  Kaplan, Jenifer B.; Reinke, Aaron W.; Keating, Amy E.
  Protein Science (2014), 23 (7), 940-953CODEN: PRCIEI; ISSN:1469-896X. (Wiley-Blackwell)
  The coiled-coil dimer is a prevalent protein interaction motif that is important for many cellular processes. The basic leucine-zipper (bZIP) transcription factors are one family of proteins for which coiled-coil mediated dimerization is essential for function, and misregulation of bZIPs can lead to disease states including cancer. This makes coiled coils attractive protein-protein interaction targets to disrupt using engineered mols. Previous work designing peptides to compete with native coiled-coil interactions focused primarily on designing the core residues of the interface to achieve affinity and specificity. However, folding studies on the model bZIP GCN4 show that coiled-coil surface residues also contribute to binding affinity. Here we extend a prior study in which peptides were designed to bind tightly and specifically to representative members of each of 20 human bZIP families. These "anti-bZIP" peptides were designed with an emphasis on target-binding specificity, with contributions to design-target specificity and affinity engineered considering only the coiled-coil core residues. High-throughput testing using peptide arrays indicated many successes. We have now measured the binding affinities and specificities of anti-bZIPs that bind to FOS, XBP1, ATF6, and CREBZF in soln. and tested whether redesigning the surface residues can increase design-target affinity. Incorporating residues that favor helix formation into the designs increased binding affinities in all cases, providing low-nanomolar binders of each target. However, changes in surface electrostatic interactions sometimes changed the binding specificity of the designed peptides.
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26. 26
  Vilanova, C., Tanner, K., Dorado-Morales, P., Villaescusa, P., Chugani, D., Frias, A., Segredo, E., Molero, X., Fritschi, M., Morales, L., Ramon, D., Pena, C., Pereto, J., and Porcar, M. (2015) Standards not that standard J. Biol. Eng. 9, 4 DOI: 10.1186/s13036-015-0017-9
  There is no corresponding record for this reference.
27. 27
  Kwok, R. (2010) FIVE HARD TRUTHS FOR SYNTHETIC BIOLOGY Nature 463, 288– 290 DOI: 10.1038/463288a
  27
  Five hard truths for synthetic biology
  Kwok, Roberta
  Nature (London, United Kingdom) (2010), 463 (7279), 288-290CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  There is no expanded citation for this reference.
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28. 28
  Mason, J. M. and Arndt, K. M. (2004) Coiled coil domains: Stability, specificity, and biological implications ChemBioChem 5, 170– 176 DOI: 10.1002/cbic.200300781
  28
  Coiled coil domains: stability, specificity, and biological implications
  Mason, Jody M.; Arndt, Katja M.
  ChemBioChem (2004), 5 (2), 170-176CODEN: CBCHFX; ISSN:1439-4227. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review discusses the importance of individual amino acids in maintaining α-helical structure (intramol. interactions) within individual helixes, while promoting specific coiled-coil interactions (intermol. interactions) of correct oligomeric state and orientation.
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29. 29
  Woolfson, D. N. (2005) The design of coiled-coil structures and assemblies Adv. Protein Chem. 70, 79 DOI: 10.1016/S0065-3233(05)70004-8
  29
  The design of coiled-coil structures and assemblies
  Woolfson, Derek N.
  Advances in Protein Chemistry (2005), 70 (Fibrous Proteins: Coiled-Coils, Collagen and Elastomers), 79-112CODEN: APCHA2; ISSN:0065-3233. (Elsevier)
  A review. Protein design allows sequence-to-structure relationships in proteins to be examd. and, potentially, new protein structures and functions to be made to order. To succeed, however, the protein-design process requires reliable rules that link protein sequence to structure/function. Although the present understanding of coiled-coil folding and assembly is not complete, through numerous bioinformatics and exptl. studies there are now sufficient rules to allow confident design attempts of naturally obsd. and even novel coiled-coil motifs. This review summarizes the current design rules for coiled coils, and describes some of the key successful coiled-coil designs that were created to date. The designs range from those for relatively straightforward, naturally obsd. structures-including parallel and antiparallel dimers, trimers and tetramers, all of which were made as homomers and heteromers-to more exotic structures that expand the repertoire of Nature's coiled-coil structures. Examples in the second bracket include a probe that binds a cancer-assocd. coiled-coil protein; a tetramer with a right-handed super-coil; sticky-ended coiled coils that self-assemble to form fibers; coiled coils that switch conformational state; a 3-component 2-stranded coiled coil; and an antiparallel dimer that directs fragment complementation of larger proteins. Some of the more recent examples show an important development in the field; namely, new designs are being created with function as well as structure in mind. This will remain one of the key challenges in coiled-coil design in the next few years. Other challenges that lie ahead include the need to discover more rules for coiled-coil prediction and design, and to implement these in prediction and design algorithms. The considerable success of coiled-coil design so far bodes well for this, however. It is likely that these challenges will be met and surpassed.
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30. 30
  Gradisar, H., Bozic, S., Doles, T., Vengust, D., Hafner-Bratkovic, I., Mertelj, A., Webb, B., Sali, A., Klavzar, S., and Jerala, R. (2013) Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments Nat. Chem. Biol. 9, 362 DOI: 10.1038/nchembio.1248
  30
  Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments
  Gradisar, Helena; Bozic, Sabina; Doles, Tibor; Vengust, Damjan; Hafner-Bratkovic, Iva; Mertelj, Alenka; Webb, Ben; Sali, Andrej; Klavzar, Sandi; Jerala, Roman
  Nature Chemical Biology (2013), 9 (6), 362-366CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  Protein structures evolved through a complex interplay of cooperative interactions, and it is still very challenging to design new protein folds de novo. Here we present a strategy to design self-assembling polypeptide nanostructured polyhedra based on modularization using orthogonal dimerizing segments. We designed and exptl. demonstrated the formation of the tetrahedron that self-assembles from a single polypeptide chain comprising 12 concatenated coiled coil-forming segments sepd. by flexible peptide hinges. The path of the polypeptide chain is guided by a defined order of segments that traverse each of the six edges of the tetrahedron exactly twice, forming coiled-coil dimers with their corresponding partners. The coincidence of the polypeptide termini in the same vertex is demonstrated by reconstituting a split fluorescent protein in the polypeptide with the correct tetrahedral topol. Polypeptides with a deleted or scrambled segment order fail to self-assemble correctly. This design platform provides a foundation for constructing new topol. polypeptide folds based on the set of orthogonal interacting polypeptide segments.
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31. 31
  Raman, S., Machaidze, G., Lustig, A., Aebi, U., and Burkhard, P. (2006) Structure-based design of peptides that self-assemble into regular polyhedral nanoparticles Nanomedicine 2, 95– 102 DOI: 10.1016/j.nano.2006.04.007
  31
  Structure-based design of peptides that self-assemble into regular polyhedral nanoparticles
  Raman, Senthilkumar; Machaidze, Gia; Lustig, Ariel; Aebi, Ueli; Burkhard, Peter
  Nanomedicine (2006), 2 (2), 95-102CODEN: NANOBF; ISSN:1549-9634. (Elsevier)
  Artificial particulate systems such as polymeric beads and liposomes are being applied in drug delivery, drug targeting, antigen display, vaccination, and other technologies. Here we used computer modeling to design a novel type of nanoparticles composed of peptides as building blocks. We verified the computer models via solid-phase peptide synthesis and biophys. analyses. We describe the structure-based design of a novel type of nanoparticles with regular polyhedral symmetry and a diam. of about 16 nm, which self-assembles from single polypeptide chains. Each peptide chain is composed of two coiled coil oligomerization domains with different oligomerization states joined by a short linker segment. In aq. soln. the peptides form nanoparticles of about 16 nm diam. Such peptide nanoparticles are ideally suited for medical applications such as drug targeting and drug delivery systems, such as imaging devices, or they may be used for repetitive antigen display.
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32. 32
  Burgess, N. C., Sharp, T. H., Thomas, F., Wood, C. W., Thomson, A. R., Zaccai, N. R., Brady, R. L., Serpell, L. C., and Woolfson, D. N. (2015) Modular Design of Self-Assembling Peptide-Based Nanotubes J. Am. Chem. Soc. 137, 10554– 10562 DOI: 10.1021/jacs.5b03973
  32
  Modular Design of Self-Assembling Peptide-Based Nanotubes
  Burgess, Natasha C.; Sharp, Thomas H.; Thomas, Franziska; Wood, Christopher W.; Thomson, Andrew R.; Zaccai, Nathan R.; Brady, R. Leo; Serpell, Louise C.; Woolfson, Derek N.
  Journal of the American Chemical Society (2015), 137 (33), 10554-10562CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  An ability to design peptide-based nanotubes (PNTs) rationally with defined and mutable internal channels would advance understanding of peptide self-assembly, and present new biomaterials for nanotechnol. and medicine. PNTs have been made from Fmoc dipeptides, cyclic peptides, and lock-washer helical bundles. Here we show that blunt-ended α-helical barrels, i.e., preassembled bundles of α-helixes with central channels, can be used as building blocks for PNTs. This approach is general and systematic, and uses a set of de novo helical bundles as stds. One of these bundles, a hexameric α-helical barrel, assembles into highly ordered PNTs, for which we have detd. a structure by combining cryo-transmission electron microscopy, X-ray fiber diffraction, and model building. The structure reveals that the overall symmetry of the peptide module plays a crit. role in ripening and ordering of the supramol. assembly. PNTs based on pentameric, hexameric, and heptameric α-helical barrels sequester hydrophobic dye within their lumens.
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33. 33
  Fletcher, J. M., Boyle, A. L., Bruning, M., Bartlett, G. J., Vincent, T. L., Zaccai, N. R., Armstrong, C. T., Bromley, E. H. C., Booth, P. J., and Brady, R. L. 2012, A Basis Set of de Novo Coiled-Coil Peptide Oligomers for Rational Protein Design and Synthetic Biology ACS Synth. Biol. 1, 240– 250 DOI: 10.1021/sb300028q
  33
  A Basis Set of de Novo Coiled-Coil Peptide Oligomers for Rational Protein Design and Synthetic Biology
  Fletcher, Jordan M.; Boyle, Aimee L.; Bruning, Marc; Bartlett, Gail J.; Vincent, Thomas L.; Zaccai, Nathan R.; Armstrong, Craig T.; Bromley, Elizabeth H. C.; Booth, Paula J.; Brady, R. Leo; Thomson, Andrew R.; Woolfson, Derek N.
  ACS Synthetic Biology (2012), 1 (6), 240-250CODEN: ASBCD6; ISSN:2161-5063. (American Chemical Society)
  Protein engineering, chem. biol., and synthetic biol. would benefit from toolkits of peptide and protein components that could be exchanged reliably between systems while maintaining their structural and functional integrity. Ideally, such components should be highly defined and predictable in all respects of sequence, structure, stability, interactions, and function. To establish one such toolkit, here we present a basis set of de novo designed α-helical coiled-coil peptides that adopt defined and well-characterized parallel dimeric, trimeric, and tetrameric states. The designs are based on sequence-to-structure relationships both from the literature and anal. of a database of known coiled-coil X-ray crystal structures. These give foreground sequences to specify the targeted oligomer state. A key feature of the design process is that sequence positions outside of these sites are considered non-essential for structural specificity; as such, they are referred to as the background, are kept non-descript, and are available for mutation as required later. Synthetic peptides were characterized in soln. by circular-dichroism spectroscopy and anal. ultracentrifugation, and their structures were detd. by X-ray crystallog. Intriguingly, a hitherto widely used empirical rule-of-thumb for coiled-coil dimer specification does not hold in the designed system. However, the desired oligomeric state is achieved by database-informed redesign of that particular foreground and confirmed exptl. We envisage that the basis set will be of use in directing and controlling protein assembly, with potential applications in chem. and synthetic biol. To help with such endeavors, we introduce Pcomp, an online registry of peptide components for protein-design and synthetic-biol. applications.
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34. 34
  Fletcher, J. M., Harniman, R. L., Barnes, F. R. H., Boyle, A. L., Collins, A., Mantell, J., Sharp, T. H., Antognozzi, M., Booth, P. J., and Linden, N. 2013, Self-Assembling Cages from Coiled-Coil Peptide Modules Science 340, 595– 599 DOI: 10.1126/science.1233936
  34
  Self-Assembling Cages from Coiled-Coil Peptide Modules
  Fletcher, Jordan M.; Harniman, Robert L.; Barnes, Frederick R. H.; Boyle, Aimee L.; Collins, Andrew; Mantell, Judith; Sharp, Thomas H.; Antognozzi, Massimo; Booth, Paula J.; Linden, Noah; Miles, Mervyn J.; Sessions, Richard B.; Verkade, Paul; Woolfson, Derek N.
  Science (Washington, DC, United States) (2013), 340 (6132), 595-599CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  An ability to mimic the boundaries of biol. compartments would improve our understanding of self-assembly and provide routes to new materials for the delivery of drugs and biologicals and the development of protocells. We show that short designed peptides can be combined to form unilamellar spheres approx. 100 nm in diam. The design comprises two, noncovalent, heterodimeric and homotrimeric coiled-coil bundles. These are joined back to back to render two complementary hubs, which when mixed form hexagonal networks that close to form cages. This design strategy offers control over chem., self-assembly, reversibility, and size of such particles.
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35. 35
  Grigoryan, G. and Keating, A. E. (2006) Structure-based prediction of bZIP partnering specificity J. Mol. Biol. 355, 1125– 1142 DOI: 10.1016/j.jmb.2005.11.036
  35
  Structure-based Prediction of bZIP Partnering Specificity
  Grigoryan, Gevorg; Keating, Amy E.
  Journal of Molecular Biology (2006), 355 (5), 1125-1142CODEN: JMOBAK; ISSN:0022-2836. (Elsevier B.V.)
  Predicting protein interaction specificity from sequence is an important goal in computational biol. We present a model for predicting the interaction preferences of coiled-coil peptides derived from bZIP transcription factors that performs very well when tested against exptl. protein microarray data. We used only sequence information to build at.-resoln. structures for 1711 dimeric complexes, and evaluated these with a variety of functions based on physics, learned empirical wts. or exptl. coupling energies. A purely phys. model, similar to those used for protein design studies, gave reasonable performance. The results were improved significantly when helix propensities were used in place of a structurally explicit model to represent the unfolded ref. state. Further improvement resulted upon accounting for residue-residue interactions in competing states in a generic way. Purely phys. structure-based methods had difficulty capturing core interactions accurately, esp. those involving polar residues such as asparagine. When these terms were replaced with wts. from a machine-learning approach, the resulting model was able to correctly order the stabilities of over 6000 pairs of complexes with greater than 90% accuracy. The final model is phys. interpretable, and suggests specific pairs of residues that are important for bZIP interaction specificity. Our results illustrate the power and potential of structural modeling as a method for predicting protein interactions and highlight obstacles that must be overcome to reach quant. accuracy using a de novo approach. Our method shows unprecedented performance in predicting protein-protein interaction specificity accurately using structural modeling and suggests that predicting coiled-coil interactions generally may be within reach.
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36. 36
  Ramisch, S., Lizatovic, R., and Andre, I. (2015) Exploring alternate states and oligomerization preferences of coiled-coils by de novo structure modeling Proteins: Struct., Funct., Genet. 83, 235– 247 DOI: 10.1002/prot.24729
  There is no corresponding record for this reference.
37. 37
  Thomson, A. R., Wood, C. W., Burton, A. J., Bartlett, G. J., Sessions, R. B., Brady, R. L., and Woolfson, D. N. (2014) Computational design of water-soluble alpha-helical barrels Science 346, 485– 488 DOI: 10.1126/science.1257452
  37
  Computational design of water-soluble α-helical barrels
  Thomson, Andrew R.; Wood, Christopher W.; Burton, Antony J.; Bartlett, Gail J.; Sessions, Richard B.; Brady, R. Leo; Woolfson, Derek N.
  Science (Washington, DC, United States) (2014), 346 (6208), 485-488CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
  The design of protein sequences that fold into prescribed de novo structures is challenging. General solns. to this problem require geometric descriptions of protein folds and methods to fit sequences to these. The α-helical coiled coils present a promising class of protein for this and offer considerable scope for exploring hitherto unseen structures. For α-helical barrels, which have more than four helixes and accessible central channels, many of the possible structures remain unobserved. Here, we combine geometrical considerations, knowledge-based scoring, and atomistic modeling to facilitate the design of new channel-contg. α-helical barrels. X-ray crystal structures of the resulting designs match predicted in silico models. Furthermore, the obsd. channels are chem. defined and have diams. related to oligomer state, which present routes to design protein function.
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38. 38
  Boyle, A. L., Bromley, E. H. C., Bartlett, G. J., Sessions, R. B., Sharp, T. H., Williams, C. L., Curmi, P. M. G., Forde, N. R., Linke, H., and Woolfson, D. N. (2012) Squaring the Circle in Peptide Assembly: From Fibers to Discrete Nanostructures by de Novo Design J. Am. Chem. Soc. 134, 15457– 15467 DOI: 10.1021/ja3053943
  38
  Squaring the Circle in Peptide Assembly: From Fibers to Discrete Nanostructures by de Novo Design
  Boyle, Aimee L.; Bromley, Elizabeth H. C.; Bartlett, Gail J.; Sessions, Richard B.; Sharp, Thomas H.; Williams, Claire L.; Curmi, Paul M. G.; Forde, Nancy R.; Linke, Heiner; Woolfson, Derek N.
  Journal of the American Chemical Society (2012), 134 (37), 15457-15467CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  The design of bioinspired nanostructures and materials of defined size and shape is challenging as it pushes the authors' understanding of biomol. assembly to its limits. In such endeavors, DNA is the current building block of choice because of its predictable and programmable self-assembly. The use of peptide- and protein-based systems, however, has potential advantages due to their more-varied chemistries, structures and functions, and the prospects for recombinant prodn. through gene synthesis and expression. Here, the authors present the design and characterization of two complementary peptides programmed to form a parallel heterodimeric coiled coil, which the authors use as the building blocks for larger, supramol. assemblies. To achieve the latter, the two peptides are joined via peptidic linkers of variable lengths to produce a range of assemblies, from flexible fibers of indefinite length, through large colloidal-scale assemblies, down to closed and discrete nanoscale objects of defined stoichiometry. The authors posit that the different modes of assembly reflect the interplay between steric constraints imposed by short linkers and the bulk of the helixes, and entropic factors that favor the formation of many smaller objects as the linker length is increased. This approach, and the resulting linear and proteinogenic polypeptides, represents a new route for constructing complex peptide-based assemblies and biomaterials.
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39. 39
  Chen, X. Y., Zaro, J. L., and Shen, W. C. (2013) Fusion protein linkers: Property, design and functionality Adv. Drug Delivery Rev. 65, 1357– 1369 DOI: 10.1016/j.addr.2012.09.039
  39
  Fusion protein linkers: Property, design and functionality
  Chen, Xiaoying; Zaro, Jennica L.; Shen, Wei-Chiang
  Advanced Drug Delivery Reviews (2013), 65 (10), 1357-1369CODEN: ADDREP; ISSN:0169-409X. (Elsevier B.V.)
  A review. As an indispensable component of recombinant fusion proteins, linkers have shown increasing importance in the construction of stable, bioactive fusion proteins. This review covers the current knowledge of fusion protein linkers and summarizes examples for their design and application. The general properties of linkers derived from naturally-occurring multi-domain proteins can be considered as the foundation in linker design. Empirical linkers designed by researchers are generally classified into 3 categories according to their structures: flexible linkers, rigid linkers, and in vivo cleavable linkers. Besides the basic role in linking the functional domains together (as in flexible and rigid linkers) or releasing the free functional domain in vivo (as in in vivo cleavable linkers), linkers may offer many other advantages for the prodn. of fusion proteins, such as improving biol. activity, increasing expression yield, and achieving desirable pharmacokinetic profiles.
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40. 40
  Bromley, E. H. C., Sessions, R. B., Thomson, A. R., and Woolfson, D. N. (2009) Designed alpha-Helical Tectons for Constructing Multicomponent Synthetic Biological Systems J. Am. Chem. Soc. 131, 928– 930 DOI: 10.1021/ja804231a
  There is no corresponding record for this reference.
41. 41
  Cerpa, R., Cohen, F. E., and Kuntz, I. D. (1996) Conformational switching in designed peptides: The helix/sheet transition Folding Des. 1, 91– 101 DOI: 10.1016/S1359-0278(96)00018-1
  41
  Conformational switching in designed peptides: the helix/sheet transition
  Cerpa, Robert; Cohen, Fred E.; Kuntz, Irwin D.
  Folding & Design (1996), 1 (2), 91-101CODEN: FODEFH; ISSN:1359-0278. (Current Biology)
  The structure adopted by peptides and proteins depends not only on the primary sequence, but also on conditions such as solvent polarity or method of sample prepn. We examd. the effect that soln. conditions have on the folded conformations of two peptides, one of which contains the photoisomerizable amino acid p-phenylazo-L-phenylalanine. Spectroscopic studies indicate that these two peptides switch between helical and β sheet conformations. The switch behavior is influenced by soln. conditions including pH, NaCl concn., temp., and peptide concn. The CD spectrum of the peptide contg. p-phenylazo-L-phenylalanine changes from a spectrum characteristic of a β sheet to one characteristic of an α helix upon irradn. We hypothesize that the structural states of the peptides are a monomeric α helix and an aggregated antiparallel β sheet. Conditions encouraging aggregation tend to favor sheet; conditions discouraging aggregation tend to favor helix. Consideration of such soln.-dependent conformational changes may affect de novo protein design and have a bearing on certain biol. processes.
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42. 42
  Webber, M. J., Newcomb, C. J., Bitton, R., and Stupp, S. I. (2011) Switching of self-assembly in a peptide nanostructure with a specific enzyme Soft Matter 7, 9665– 9672 DOI: 10.1039/c1sm05610g
  42
  Switching of self-assembly in a peptide nanostructure with a specific enzyme
  Webber, Matthew J.; Newcomb, Christina J.; Bitton, Ronit; Stupp, Samuel I.
  Soft Matter (2011), 7 (20), 9665-9672CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
  Peptide self-assembly has been shown to be a useful tool for the prepn. of bioactive nanostructures, and recent work has demonstrated their potential as therapies for regenerative medicine. In principle, one route to make these nanostructures more biomimetic would be to incorporate in their mol. design the capacity for biol. sensing. We report here on the use of a reversible enzymic trigger to control the assembly and disassembly of peptide amphiphile (PA) nanostructures. The PA used in these studies contained a consensus substrate sequence specific to protein kinase A (PKA), a biol. enzyme important for intracellular signaling that has also been shown to be an extracellular cancer biomarker. Upon treatment with PKA, this PA mol. becomes phosphorylated causing the high aspect-ratio filamentous PA nanostructures to disassemble. Treatment with an enzyme to cleave the phosphate group results in reformation of the filamentous nanostructures. We also show that disassembly in the presence of PKA allows the enzyme-triggered release of an encapsulated cancer drug. In addn., these drug-loaded nanostructures were found to induce preferential cytotoxicity in a cancer cell line that is known to secrete high levels of PKA. This ability to control nanostructure through an enzymic switch could allow for the prepn. of highly sophisticated and biomimetic materials that incorporate a biol. sensing capability to enable therapeutic specificity.
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43. 43
  Zimenkov, Y., Dublin, S. N., Ni, R., Tu, R. S., Breedveld, V., Apkarian, R. P., and Conticello, V. P. (2006) Rational design of a reversible pH-responsive switch for peptide self-assembly J. Am. Chem. Soc. 128, 6770– 6771 DOI: 10.1021/ja0605974
  43
  Rational design of a reversible pH-responsive switch for peptide self-assembly
  Zimenkov, Yuri; Dublin, Steven N.; Ni, Rong; Tu, Raymond S.; Breedveld, Victor; Apkarian, Robert P.; Conticello, Vincent P.
  Journal of the American Chemical Society (2006), 128 (21), 6770-6771CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
  Peptide TZ1H, based on the heptad sequence of a coiled-coil trimer, undergoes fully reversible, pH-dependent self-assembly into long-aspect-ratio helical fibers. Substitution of isoleucine residues with histidine at the core d-positions of alternate heptads introduces a mechanism by which self-assembly is coupled to the protonation state of the imidazole side chain. CD spectroscopy, transmission electron microscopy, and microrheol. techniques revealed that the self-assembly of TZ1H coincides with a distinct coil-helix conformational transition that occurs within a narrow pH range near the pKa of the imidazole side chains of the core histidine residues.
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Supporting Information
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssynbio.7b00037.
- Additional circular dichroism data; dynamic light scattering data; AUC fitting information; MALDI data (PDF)
- sb7b00037_si_001.pdf (268.15 kb)
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