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Structural resolution of switchable states of a de novo peptide assembly
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943578/ https://www.ncbi.nlm.nih.gov/pubmed/33750792 http://dx.doi.org/10.1038/s41467-021-21851-8 |
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author | Dawson, William M. Lang, Eric J. M. Rhys, Guto G. Shelley, Kathryn L. Williams, Christopher Brady, R. Leo Crump, Matthew P. Mulholland, Adrian J. Woolfson, Derek N. |
author_facet | Dawson, William M. Lang, Eric J. M. Rhys, Guto G. Shelley, Kathryn L. Williams, Christopher Brady, R. Leo Crump, Matthew P. Mulholland, Adrian J. Woolfson, Derek N. |
author_sort | Dawson, William M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7943578 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79435782021-03-28 Structural resolution of switchable states of a de novo peptide assembly Dawson, William M. Lang, Eric J. M. Rhys, Guto G. Shelley, Kathryn L. Williams, Christopher Brady, R. Leo Crump, Matthew P. Mulholland, Adrian J. Woolfson, Derek N. Nat Commun Article 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. Nature Publishing Group UK 2021-03-09 /pmc/articles/PMC7943578/ /pubmed/33750792 http://dx.doi.org/10.1038/s41467-021-21851-8 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Dawson, William M. Lang, Eric J. M. Rhys, Guto G. Shelley, Kathryn L. Williams, Christopher Brady, R. Leo Crump, Matthew P. Mulholland, Adrian J. Woolfson, Derek N. Structural resolution of switchable states of a de novo peptide assembly |
title | Structural resolution of switchable states of a de novo peptide assembly |
title_full | Structural resolution of switchable states of a de novo peptide assembly |
title_fullStr | Structural resolution of switchable states of a de novo peptide assembly |
title_full_unstemmed | Structural resolution of switchable states of a de novo peptide assembly |
title_short | Structural resolution of switchable states of a de novo peptide assembly |
title_sort | structural resolution of switchable states of a de novo peptide assembly |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943578/ https://www.ncbi.nlm.nih.gov/pubmed/33750792 http://dx.doi.org/10.1038/s41467-021-21851-8 |
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