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Biomolecules 2019, 9(4), 146; https://doi.org/10.3390/biom9040146

Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins

1
Division of Research Informatics, Beckman Research Institute at City of Hope National Medical Center, Duarte, CA 91010, USA
2
Center for Theoretical Biological Physics, Rice University, Houston, TX 77030, USA
3
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
*
Author to whom correspondence should be addressed.
Received: 5 March 2019 / Revised: 9 April 2019 / Accepted: 10 April 2019 / Published: 11 April 2019
(This article belongs to the Special Issue Intrinsically Disordered Proteins and Chronic Diseases)
PDF [1797 KB, uploaded 11 April 2019]

Abstract

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.
Keywords: intrinsically disordered protein; conformational ensemble; nuclear magnetic resonance; replica exchange molecular dynamics; drug design intrinsically disordered protein; conformational ensemble; nuclear magnetic resonance; replica exchange molecular dynamics; drug design
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Bhattacharya, S.; Lin, X. Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins. Biomolecules 2019, 9, 146.

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