Abstract
The molecular dynamics (MD) method is a promising approach toward elucidating the molecular mechanisms of intrinsically disordered regions (IDRs) of proteins and their fuzzy complexes. This mini-review introduces recent studies that apply MD simulations to investigate the molecular recognition of IDRs. Firstly, methodological issues by which MD simulations treat IDRs, such as developing force fields, treating periodic boundary conditions, and enhanced sampling approaches, are discussed. Then, several examples of the applications of MD to investigate molecular interactions of IDRs in terms of the two kinds of complex formations; coupled-folding and binding and fuzzy complex. MD simulations provide insight into the molecular mechanisms of these binding processes by sampling conformational ensembles of flexible IDRs. In particular, we focused on all-atom explicit-solvent MD simulations except for studies of higher-order assembly of IDRs. Recent advances in MD methods, and computational power make it possible to dissect the molecular details of realistic molecular systems involving the dynamic behavior of IDRs.
Highlights
Many force fields are parameterized to fit the properties of structured proteins and are not suitable to apply to intrinsically disordered regions (IDRs)
Simulations for IDRs have several difficulties: (i) force fields tailored for structured proteins are not suitable for IDRs (ii) large fractions of charged residues in IDRs would cause artifacts of electrostatic potentials originating from the periodic boundary condition (PBC) (iii) high conformational heterogeneity of IDRs makes exploration of the conformational space difficult
Some IDR-oriented force fields have successfully yielded conformational ensembles that agree with a variety of experimental observations
Summary
Within the past several decades, protein science has focused primarily on the correlation among sequence, structure, and function of proteins based on Anfinsen's dogma, stating that the amino acid sequence of a protein encodes its three-dimensional (3D) structure [1]. “Coupled-folding and binding” is a typical protein conformation scenario in which a stable protein conformation is formed only when IDRs are recognized by a receptor [8] In this mechanism, IDRs only partly conform to the sequence–structure–function paradigm because their functions are conducted with their specific structures in the bound state. The MD method simulates the evolution in time of a given molecular system described as a set of atomic coordinates (and velocities) in Cartesian space This method requires considerable computational costs, recent advances in computational power, algorithms, and methods have made it possible to analyze large molecular systems over long time scales. In this mini-review, we introduce recent advances in MD studies on IDRs and their fuzzy complexes. The sections “Coupled-folding and binding” and “Fuzzy complexes” present recent applications of the MD method to dissect the molecular mechanisms of IDRs
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