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Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This en...

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Autores principales: Bhattacharya, Supriyo, Lin, Xingcheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523529/
https://www.ncbi.nlm.nih.gov/pubmed/30979035
http://dx.doi.org/10.3390/biom9040146
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author Bhattacharya, Supriyo
Lin, Xingcheng
author_facet Bhattacharya, Supriyo
Lin, Xingcheng
author_sort Bhattacharya, Supriyo
collection PubMed
description Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field.
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spelling pubmed-65235292019-06-03 Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins Bhattacharya, Supriyo Lin, Xingcheng Biomolecules Review Intrinsically disordered proteins (IDP) are abundant in the human genome and have recently emerged as major therapeutic targets for various diseases. Unlike traditional proteins that adopt a definitive structure, IDPs in free solution are disordered and exist as an ensemble of conformations. This enables the IDPs to signal through multiple signaling pathways and serve as scaffolds for multi-protein complexes. The challenge in studying IDPs experimentally stems from their disordered nature. Nuclear magnetic resonance (NMR), circular dichroism, small angle X-ray scattering, and single molecule Förster resonance energy transfer (FRET) can give the local structural information and overall dimension of IDPs, but seldom provide a unified picture of the whole protein. To understand the conformational dynamics of IDPs and how their structural ensembles recognize multiple binding partners and small molecule inhibitors, knowledge-based and physics-based sampling techniques are utilized in-silico, guided by experimental structural data. However, efficient sampling of the IDP conformational ensemble requires traversing the numerous degrees of freedom in the IDP energy landscape, as well as force-fields that accurately model the protein and solvent interactions. In this review, we have provided an overview of the current state of computational methods for studying IDP structure and dynamics and discussed the major challenges faced in this field. MDPI 2019-04-11 /pmc/articles/PMC6523529/ /pubmed/30979035 http://dx.doi.org/10.3390/biom9040146 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Bhattacharya, Supriyo
Lin, Xingcheng
Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
title Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
title_full Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
title_fullStr Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
title_full_unstemmed Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
title_short Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins
title_sort recent advances in computational protocols addressing intrinsically disordered proteins
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523529/
https://www.ncbi.nlm.nih.gov/pubmed/30979035
http://dx.doi.org/10.3390/biom9040146
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