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Assessing the effect of dynamics on the closed-loop protein-folding hypothesis

The closed-loop (loop-n-lock) hypothesis of protein folding suggests that loops of about 25 residues, closed through interactions between the loop ends (locks), play an important role in protein structure. Coarse-grain elastic network simulations, and examination of loop lengths in a diverse set of...

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Autores principales: Chintapalli, Sree V., Illingworth, Christopher J. R., Upton, Graham J. G., Sacquin-Mora, Sophie, Reeves, Philip J., Mohammedali, Hani S., Reynolds, Christopher A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869168/
https://www.ncbi.nlm.nih.gov/pubmed/24258160
http://dx.doi.org/10.1098/rsif.2013.0935
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author Chintapalli, Sree V.
Illingworth, Christopher J. R.
Upton, Graham J. G.
Sacquin-Mora, Sophie
Reeves, Philip J.
Mohammedali, Hani S.
Reynolds, Christopher A.
author_facet Chintapalli, Sree V.
Illingworth, Christopher J. R.
Upton, Graham J. G.
Sacquin-Mora, Sophie
Reeves, Philip J.
Mohammedali, Hani S.
Reynolds, Christopher A.
author_sort Chintapalli, Sree V.
collection PubMed
description The closed-loop (loop-n-lock) hypothesis of protein folding suggests that loops of about 25 residues, closed through interactions between the loop ends (locks), play an important role in protein structure. Coarse-grain elastic network simulations, and examination of loop lengths in a diverse set of proteins, each supports a bias towards loops of close to 25 residues in length between residues of high stability. Previous studies have established a correlation between total contact distance (TCD), a metric of sequence distances between contacting residues (cf. contact order), and the log-folding rate of a protein. In a set of 43 proteins, we identify an improved correlation (r(2) = 0.76), when the metric is restricted to residues contacting the locks, compared to the equivalent result when all residues are considered (r(2) = 0.65). This provides qualified support for the hypothesis, albeit with an increased emphasis upon the importance of a much larger set of residues surrounding the locks. Evidence of a similar-sized protein core/extended nucleus (with significant overlap) was obtained from TCD calculations in which residues were successively eliminated according to their hydrophobicity and connectivity, and from molecular dynamics simulations. Our results suggest that while folding is determined by a subset of residues that can be predicted by application of the closed-loop hypothesis, the original hypothesis is too simplistic; efficient protein folding is dependent on a considerably larger subset of residues than those involved in lock formation.
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spelling pubmed-38691682014-02-06 Assessing the effect of dynamics on the closed-loop protein-folding hypothesis Chintapalli, Sree V. Illingworth, Christopher J. R. Upton, Graham J. G. Sacquin-Mora, Sophie Reeves, Philip J. Mohammedali, Hani S. Reynolds, Christopher A. J R Soc Interface Research Articles The closed-loop (loop-n-lock) hypothesis of protein folding suggests that loops of about 25 residues, closed through interactions between the loop ends (locks), play an important role in protein structure. Coarse-grain elastic network simulations, and examination of loop lengths in a diverse set of proteins, each supports a bias towards loops of close to 25 residues in length between residues of high stability. Previous studies have established a correlation between total contact distance (TCD), a metric of sequence distances between contacting residues (cf. contact order), and the log-folding rate of a protein. In a set of 43 proteins, we identify an improved correlation (r(2) = 0.76), when the metric is restricted to residues contacting the locks, compared to the equivalent result when all residues are considered (r(2) = 0.65). This provides qualified support for the hypothesis, albeit with an increased emphasis upon the importance of a much larger set of residues surrounding the locks. Evidence of a similar-sized protein core/extended nucleus (with significant overlap) was obtained from TCD calculations in which residues were successively eliminated according to their hydrophobicity and connectivity, and from molecular dynamics simulations. Our results suggest that while folding is determined by a subset of residues that can be predicted by application of the closed-loop hypothesis, the original hypothesis is too simplistic; efficient protein folding is dependent on a considerably larger subset of residues than those involved in lock formation. The Royal Society 2014-02-06 /pmc/articles/PMC3869168/ /pubmed/24258160 http://dx.doi.org/10.1098/rsif.2013.0935 Text en http://creativecommons.org/licenses/by/3.0/ © 2013 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Research Articles
Chintapalli, Sree V.
Illingworth, Christopher J. R.
Upton, Graham J. G.
Sacquin-Mora, Sophie
Reeves, Philip J.
Mohammedali, Hani S.
Reynolds, Christopher A.
Assessing the effect of dynamics on the closed-loop protein-folding hypothesis
title Assessing the effect of dynamics on the closed-loop protein-folding hypothesis
title_full Assessing the effect of dynamics on the closed-loop protein-folding hypothesis
title_fullStr Assessing the effect of dynamics on the closed-loop protein-folding hypothesis
title_full_unstemmed Assessing the effect of dynamics on the closed-loop protein-folding hypothesis
title_short Assessing the effect of dynamics on the closed-loop protein-folding hypothesis
title_sort assessing the effect of dynamics on the closed-loop protein-folding hypothesis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869168/
https://www.ncbi.nlm.nih.gov/pubmed/24258160
http://dx.doi.org/10.1098/rsif.2013.0935
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