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Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding
Protein-protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at high resolution. Here we exploited ubiquitin’s noncovalent dimerization equilibrium to assess the potential...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448524/ https://www.ncbi.nlm.nih.gov/pubmed/26023027 http://dx.doi.org/10.1038/srep10549 |
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author | Abriata, Luciano A. Dal Peraro, Matteo |
author_facet | Abriata, Luciano A. Dal Peraro, Matteo |
author_sort | Abriata, Luciano A. |
collection | PubMed |
description | Protein-protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at high resolution. Here we exploited ubiquitin’s noncovalent dimerization equilibrium to assess the potential of atomistic simulations to reproduce reversible protein-protein binding, by running submicrosecond simulations of systems with multiple copies of the protein at millimolar concentrations. The simulations essentially fail because they lead to aggregates, yet they reproduce some specificity in the binding interfaces as observed in known covalent and noncovalent ubiquitin dimers. Following similar observations in literature we hint at electrostatics and water descriptions as the main liable force field elements, and propose that their optimization should consider observables relevant to multi-protein systems and unfolded proteins. Within limitations, analysis of binding events suggests salient features of protein-protein recognition and binding, to be retested with improved force fields. Among them, that specific configurations of relative direction and orientation seem to trigger fast binding of two molecules, even over 50 Å distances; that conformational selection can take place within surface-to-surface distances of 10 to 40 Å i.e. well before actual intermolecular contact; and that establishment of contacts between molecules further locks their conformations and relative orientations. |
format | Online Article Text |
id | pubmed-4448524 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-44485242015-06-10 Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding Abriata, Luciano A. Dal Peraro, Matteo Sci Rep Article Protein-protein recognition and binding are governed by diffusion, noncovalent forces and conformational flexibility, entangled in a way that only molecular dynamics simulations can dissect at high resolution. Here we exploited ubiquitin’s noncovalent dimerization equilibrium to assess the potential of atomistic simulations to reproduce reversible protein-protein binding, by running submicrosecond simulations of systems with multiple copies of the protein at millimolar concentrations. The simulations essentially fail because they lead to aggregates, yet they reproduce some specificity in the binding interfaces as observed in known covalent and noncovalent ubiquitin dimers. Following similar observations in literature we hint at electrostatics and water descriptions as the main liable force field elements, and propose that their optimization should consider observables relevant to multi-protein systems and unfolded proteins. Within limitations, analysis of binding events suggests salient features of protein-protein recognition and binding, to be retested with improved force fields. Among them, that specific configurations of relative direction and orientation seem to trigger fast binding of two molecules, even over 50 Å distances; that conformational selection can take place within surface-to-surface distances of 10 to 40 Å i.e. well before actual intermolecular contact; and that establishment of contacts between molecules further locks their conformations and relative orientations. Nature Publishing Group 2015-05-29 /pmc/articles/PMC4448524/ /pubmed/26023027 http://dx.doi.org/10.1038/srep10549 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Abriata, Luciano A. Dal Peraro, Matteo Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
title | Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
title_full | Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
title_fullStr | Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
title_full_unstemmed | Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
title_short | Assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
title_sort | assessing the potential of atomistic molecular dynamics simulations to probe reversible protein-protein recognition and binding |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448524/ https://www.ncbi.nlm.nih.gov/pubmed/26023027 http://dx.doi.org/10.1038/srep10549 |
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