Insights into the binding of intrinsically disordered proteins from molecular dynamics simulation
TLDR
The progress that has been made in the study of coupled folding and binding using molecular dynamics simulation is examined, and what has been learnt is summarized and the state of the art is examined in terms of both methodologies and models.Abstract:
Intrinsically disordered proteins (IDPs) are a class of protein that, in the native state, possess no well-defined secondary or tertiary structure, existing instead as dynamic ensembles of conformations They are biologically important, with approximately 20% of all eukaryotic proteins disordered, and found at the heart of many biochemical networks To fulfil their biological roles, many IDPs need to bind to proteins and/or nucleic acids And although unstructured in solution, IDPs typically fold into a well-defined three-dimensional structure upon interaction with a binding partner The flexibility and structural diversity inherent to IDPs makes this coupled folding and binding difficult to study at atomic resolution by experiment alone, and computer simulation currently offers perhaps the best opportunity to understand this process But simulation of coupled folding and binding is itself extremely challenging; these molecules are large and highly flexible, and their binding partners, such as DNA or cyclins, are also often large Therefore, their study requires either simplified representations, advanced enhanced sampling schemes, or both It is not always clear that existing simulation techniques, optimized for studying folded proteins, are well suited to IDPs In this article, we examine the progress that has been made in the study of coupled folding and binding using molecular dynamics simulation We summarize what has been learnt, and examine the state of the art in terms of both methodologies and models We also consider the lessons to be learnt from advances in other areas of simulation and highlight the issues that remain of be addressedread more
Citations
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Journal ArticleDOI
Coarse-Grained Protein Models and Their Applications
Sebastian Kmiecik,Dominik Gront,Michal Kolinski,Lukasz Wieteska,Lukasz Wieteska,Aleksandra Elzbieta Dawid,Andrzej Kolinski +6 more
TL;DR: An overview of coarse-grained models focusing on their design, including choices of representation, models of energy functions, sampling of conformational space, and applications in the modeling of protein structure, dynamics, and interactions are provided.
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Computational and theoretical advances in studies of intrinsically disordered proteins.
TL;DR: Some of the developments in simulation and theory in recent years, which have been driven by the desire to better capture IDP properties at different time- and length-scales, are summarized.
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Polarizable force fields for molecular dynamics simulations of biomolecules
TL;DR: Polarizable force fields have been widely used for the simulation of biomolecules as mentioned in this paper, and their use has been largely experimental, with their use restricted to specialized researchers, but this situation is now changing.
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Interplay between partner and ligand facilitates the folding and binding of an intrinsically disordered protein.
Joseph M. Rogers,Vladimiras Oleinikovas,Sarah L. Shammas,Chi T. Wong,David De Sancho,Christopher M. Baker,Jane Clarke +6 more
TL;DR: A small disordered protein is examined and it is found that interactions with its (already structured) partner protein are what cause the relatively unstructured protein to fold, offering some explanation for the abundance of similar protein–protein interactions throughout biology.
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Drug-Like Protein-Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology.
Bruno O. Villoutreix,Mélaine A. Kuenemann,Jean-Luc Poyet,Heriberto Bruzzoni-Giovanelli,Céline M. Labbé,Céline M. Labbé,David Lagorce,David Lagorce,Olivier Sperandio,Olivier Sperandio,Maria A. Miteva,Maria A. Miteva +11 more
TL;DR: The field of proteinprotein interaction research is introduced, key challenges are discussed, and key challenges and comment recently reported in silico packages, protocols and databases dedicated to PPIs are discussed.
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