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Modeling disordered protein interactions from biophysical principles

Disordered protein-protein interactions (PPIs), those involving a folded protein and an intrinsically disordered protein (IDP), are prevalent in the cell, including important signaling and regulatory pathways. IDPs do not adopt a single dominant structure in isolation but often become ordered upon b...

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Autores principales: Peterson, Lenna X., Roy, Amitava, Christoffer, Charles, Terashi, Genki, Kihara, Daisuke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402988/
https://www.ncbi.nlm.nih.gov/pubmed/28394890
http://dx.doi.org/10.1371/journal.pcbi.1005485
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author Peterson, Lenna X.
Roy, Amitava
Christoffer, Charles
Terashi, Genki
Kihara, Daisuke
author_facet Peterson, Lenna X.
Roy, Amitava
Christoffer, Charles
Terashi, Genki
Kihara, Daisuke
author_sort Peterson, Lenna X.
collection PubMed
description Disordered protein-protein interactions (PPIs), those involving a folded protein and an intrinsically disordered protein (IDP), are prevalent in the cell, including important signaling and regulatory pathways. IDPs do not adopt a single dominant structure in isolation but often become ordered upon binding. To aid understanding of the molecular mechanisms of disordered PPIs, it is crucial to obtain the tertiary structure of the PPIs. However, experimental methods have difficulty in solving disordered PPIs and existing protein-protein and protein-peptide docking methods are not able to model them. Here we present a novel computational method, IDP-LZerD, which models the conformation of a disordered PPI by considering the biophysical binding mechanism of an IDP to a structured protein, whereby a local segment of the IDP initiates the interaction and subsequently the remaining IDP regions explore and coalesce around the initial binding site. On a dataset of 22 disordered PPIs with IDPs up to 69 amino acids, successful predictions were made for 21 bound and 18 unbound receptors. The successful modeling provides additional support for biophysical principles. Moreover, the new technique significantly expands the capability of protein structure modeling and provides crucial insights into the molecular mechanisms of disordered PPIs.
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spelling pubmed-54029882017-05-14 Modeling disordered protein interactions from biophysical principles Peterson, Lenna X. Roy, Amitava Christoffer, Charles Terashi, Genki Kihara, Daisuke PLoS Comput Biol Research Article Disordered protein-protein interactions (PPIs), those involving a folded protein and an intrinsically disordered protein (IDP), are prevalent in the cell, including important signaling and regulatory pathways. IDPs do not adopt a single dominant structure in isolation but often become ordered upon binding. To aid understanding of the molecular mechanisms of disordered PPIs, it is crucial to obtain the tertiary structure of the PPIs. However, experimental methods have difficulty in solving disordered PPIs and existing protein-protein and protein-peptide docking methods are not able to model them. Here we present a novel computational method, IDP-LZerD, which models the conformation of a disordered PPI by considering the biophysical binding mechanism of an IDP to a structured protein, whereby a local segment of the IDP initiates the interaction and subsequently the remaining IDP regions explore and coalesce around the initial binding site. On a dataset of 22 disordered PPIs with IDPs up to 69 amino acids, successful predictions were made for 21 bound and 18 unbound receptors. The successful modeling provides additional support for biophysical principles. Moreover, the new technique significantly expands the capability of protein structure modeling and provides crucial insights into the molecular mechanisms of disordered PPIs. Public Library of Science 2017-04-10 /pmc/articles/PMC5402988/ /pubmed/28394890 http://dx.doi.org/10.1371/journal.pcbi.1005485 Text en https://creativecommons.org/publicdomain/zero/1.0/ 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 (https://creativecommons.org/publicdomain/zero/1.0/) public domain dedication.
spellingShingle Research Article
Peterson, Lenna X.
Roy, Amitava
Christoffer, Charles
Terashi, Genki
Kihara, Daisuke
Modeling disordered protein interactions from biophysical principles
title Modeling disordered protein interactions from biophysical principles
title_full Modeling disordered protein interactions from biophysical principles
title_fullStr Modeling disordered protein interactions from biophysical principles
title_full_unstemmed Modeling disordered protein interactions from biophysical principles
title_short Modeling disordered protein interactions from biophysical principles
title_sort modeling disordered protein interactions from biophysical principles
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402988/
https://www.ncbi.nlm.nih.gov/pubmed/28394890
http://dx.doi.org/10.1371/journal.pcbi.1005485
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