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Evolutionary Conserved Positions Define Protein Conformational Diversity

Conformational diversity of the native state plays a central role in modulating protein function. The selection paradigm sustains that different ligands shift the conformational equilibrium through their binding to highest-affinity conformers. Intramolecular vibrational dynamics associated to each c...

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Autores principales: Saldaño, Tadeo E., Monzon, Alexander M., Parisi, Gustavo, Fernandez-Alberti, Sebastian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805271/
https://www.ncbi.nlm.nih.gov/pubmed/27008419
http://dx.doi.org/10.1371/journal.pcbi.1004775
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author Saldaño, Tadeo E.
Monzon, Alexander M.
Parisi, Gustavo
Fernandez-Alberti, Sebastian
author_facet Saldaño, Tadeo E.
Monzon, Alexander M.
Parisi, Gustavo
Fernandez-Alberti, Sebastian
author_sort Saldaño, Tadeo E.
collection PubMed
description Conformational diversity of the native state plays a central role in modulating protein function. The selection paradigm sustains that different ligands shift the conformational equilibrium through their binding to highest-affinity conformers. Intramolecular vibrational dynamics associated to each conformation should guarantee conformational transitions, which due to its importance, could possibly be associated with evolutionary conserved traits. Normal mode analysis, based on a coarse-grained model of the protein, can provide the required information to explore these features. Herein, we present a novel procedure to identify key positions sustaining the conformational diversity associated to ligand binding. The method is applied to an adequate refined dataset of 188 paired protein structures in their bound and unbound forms. Firstly, normal modes most involved in the conformational change are selected according to their corresponding overlap with structural distortions introduced by ligand binding. The subspace defined by these modes is used to analyze the effect of simulated point mutations on preserving the conformational diversity of the protein. We find a negative correlation between the effects of mutations on these normal mode subspaces associated to ligand-binding and position-specific evolutionary conservations obtained from multiple sequence-structure alignments. Positions whose mutations are found to alter the most these subspaces are defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. These positions are shown to be evolutionary conserved, mostly buried aliphatic residues localized in regular structural regions of the protein like β-sheets and α-helix.
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spelling pubmed-48052712016-03-25 Evolutionary Conserved Positions Define Protein Conformational Diversity Saldaño, Tadeo E. Monzon, Alexander M. Parisi, Gustavo Fernandez-Alberti, Sebastian PLoS Comput Biol Research Article Conformational diversity of the native state plays a central role in modulating protein function. The selection paradigm sustains that different ligands shift the conformational equilibrium through their binding to highest-affinity conformers. Intramolecular vibrational dynamics associated to each conformation should guarantee conformational transitions, which due to its importance, could possibly be associated with evolutionary conserved traits. Normal mode analysis, based on a coarse-grained model of the protein, can provide the required information to explore these features. Herein, we present a novel procedure to identify key positions sustaining the conformational diversity associated to ligand binding. The method is applied to an adequate refined dataset of 188 paired protein structures in their bound and unbound forms. Firstly, normal modes most involved in the conformational change are selected according to their corresponding overlap with structural distortions introduced by ligand binding. The subspace defined by these modes is used to analyze the effect of simulated point mutations on preserving the conformational diversity of the protein. We find a negative correlation between the effects of mutations on these normal mode subspaces associated to ligand-binding and position-specific evolutionary conservations obtained from multiple sequence-structure alignments. Positions whose mutations are found to alter the most these subspaces are defined as key positions, that is, dynamically important residues that mediate the ligand-binding conformational change. These positions are shown to be evolutionary conserved, mostly buried aliphatic residues localized in regular structural regions of the protein like β-sheets and α-helix. Public Library of Science 2016-03-23 /pmc/articles/PMC4805271/ /pubmed/27008419 http://dx.doi.org/10.1371/journal.pcbi.1004775 Text en © 2016 Saldaño et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Saldaño, Tadeo E.
Monzon, Alexander M.
Parisi, Gustavo
Fernandez-Alberti, Sebastian
Evolutionary Conserved Positions Define Protein Conformational Diversity
title Evolutionary Conserved Positions Define Protein Conformational Diversity
title_full Evolutionary Conserved Positions Define Protein Conformational Diversity
title_fullStr Evolutionary Conserved Positions Define Protein Conformational Diversity
title_full_unstemmed Evolutionary Conserved Positions Define Protein Conformational Diversity
title_short Evolutionary Conserved Positions Define Protein Conformational Diversity
title_sort evolutionary conserved positions define protein conformational diversity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805271/
https://www.ncbi.nlm.nih.gov/pubmed/27008419
http://dx.doi.org/10.1371/journal.pcbi.1004775
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