Structural resolution of switchable states of a de novo peptide assembly
| Autor: | Christopher Williams, William M. Dawson, Adrian J. Mulholland, Matthew P. Crump, R. Leo Brady, Eric J. M. Lang, Kathryn L Shelley, Guto G. Rhys, Derek N. Woolfson |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Steric effects Protein Conformation alpha-Helical Protein Conformation Science Protein design General Physics and Astronomy BrisSynBio Peptide Molecular Dynamics Simulation 010402 general chemistry Crystallography X-Ray Protein Engineering 01 natural sciences General Biochemistry Genetics and Molecular Biology Article Hydrophobic effect 03 medical and health sciences Molecular dynamics Amphiphile chemistry.chemical_classification Multidisciplinary Chemistry Bristol BioDesign Institute Proteins General Chemistry 0104 chemical sciences Barrel 030104 developmental biology Biophysics Solvents Protein crystallization Structural biology Peptides Hydrophobic and Hydrophilic Interactions |
| Zdroj: | Nature Communications Dawson, W M, Lang, E J M, Rhys, G G, Shelley, K L, Williams, C, Brady, R L, Crump, M P, Mulholland, A J & Woolfson, D N 2021, ' Structural resolution of switchable states of a de novo peptide assembly ', Nature Communications, vol. 12, no. 1, 1530 (2020) . https://doi.org/10.1038/s41467-021-21851-8 Nature Communications, Vol 12, Iss 1, Pp 1-10 (2021) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-21851-8 |
| Popis: | De novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By placing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally. So far most of the de novo designed proteins are for single states only. Here, the authors present the de novo design and crystal structure determination of a coiled-coil peptide that assembles into multiple, distinct conformational states under the same conditions and further characterise its properties with biophysical experiments, NMR and MD simulations. |
| Databáze: | OpenAIRE |
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