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Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations
Small globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169518/ https://www.ncbi.nlm.nih.gov/pubmed/21931542 http://dx.doi.org/10.1371/journal.pcbi.1002137 |
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author | Thukral, Lipi Daidone, Isabella Smith, Jeremy C. |
author_facet | Thukral, Lipi Daidone, Isabella Smith, Jeremy C. |
author_sort | Thukral, Lipi |
collection | PubMed |
description | Small globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide chain reaches, and leaves, the TS by completely random fluctuations, or whether there is a directed, stepwise process. Here, the folding TS of a 15-residue β-hairpin peptide, Peptide 1, is characterized using independent 2.5 μs-long unbiased atomistic molecular dynamics (MD) simulations (a total of 15 μs). The trajectories were started from fully unfolded structures. Multiple (spontaneous) folding events to the NMR-derived conformation are observed, allowing both structural and dynamical characterization of the folding TS. A common loop-like topology is observed in all the TS structures with native end-to-end and turn contacts, while the central segments of the strands are not in contact. Non-native sidechain contacts are present in the TS between the only tryptophan (W11) and the turn region (P7-G9). Prior to the TS the turn is found to be already locked by the W11 sidechain, while the ends are apart. Once the ends have also come into contact, the TS is reached. Finally, along the reactive folding paths the cooperative loss of the W11 non-native contacts and the formation of the central inter-strand native contacts lead to the peptide rapidly proceeding from the TS to the native state. The present results indicate a directed stepwise process to folding the peptide. |
format | Online Article Text |
id | pubmed-3169518 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31695182011-09-19 Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations Thukral, Lipi Daidone, Isabella Smith, Jeremy C. PLoS Comput Biol Research Article Small globular proteins and peptides commonly exhibit two-state folding kinetics in which the rate limiting step of folding is the surmounting of a single free energy barrier at the transition state (TS) separating the folded and the unfolded states. An intriguing question is whether the polypeptide chain reaches, and leaves, the TS by completely random fluctuations, or whether there is a directed, stepwise process. Here, the folding TS of a 15-residue β-hairpin peptide, Peptide 1, is characterized using independent 2.5 μs-long unbiased atomistic molecular dynamics (MD) simulations (a total of 15 μs). The trajectories were started from fully unfolded structures. Multiple (spontaneous) folding events to the NMR-derived conformation are observed, allowing both structural and dynamical characterization of the folding TS. A common loop-like topology is observed in all the TS structures with native end-to-end and turn contacts, while the central segments of the strands are not in contact. Non-native sidechain contacts are present in the TS between the only tryptophan (W11) and the turn region (P7-G9). Prior to the TS the turn is found to be already locked by the W11 sidechain, while the ends are apart. Once the ends have also come into contact, the TS is reached. Finally, along the reactive folding paths the cooperative loss of the W11 non-native contacts and the formation of the central inter-strand native contacts lead to the peptide rapidly proceeding from the TS to the native state. The present results indicate a directed stepwise process to folding the peptide. Public Library of Science 2011-09-08 /pmc/articles/PMC3169518/ /pubmed/21931542 http://dx.doi.org/10.1371/journal.pcbi.1002137 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Thukral, Lipi Daidone, Isabella Smith, Jeremy C. Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations |
title | Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations |
title_full | Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations |
title_fullStr | Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations |
title_full_unstemmed | Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations |
title_short | Structured Pathway across the Transition State for Peptide Folding Revealed by Molecular Dynamics Simulations |
title_sort | structured pathway across the transition state for peptide folding revealed by molecular dynamics simulations |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169518/ https://www.ncbi.nlm.nih.gov/pubmed/21931542 http://dx.doi.org/10.1371/journal.pcbi.1002137 |
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