Advanced Sampling Methods for Multiscale Simulation of Disordered Proteins and Dynamic Interactions

Abstract

Intrinsically disordered proteins (IDPs) are highly prevalent and play important roles in biology and human diseases. It is now also recognized that many IDPs remain dynamic even in specific complexes and functional assemblies. Computer simulations are essential for deriving a molecular description of the disordered protein ensembles and dynamic interactions for a mechanistic understanding of IDPs in biology, diseases, and therapeutics. Here, we provide an in-depth review of recent advances in the multi-scale simulation of disordered protein states, with a particular emphasis on the development and application of advanced sampling techniques for studying IDPs. These techniques are critical for adequate sampling of the manifold functionally relevant conformational spaces of IDPs. Together with dramatically improved protein force fields, these advanced simulation approaches have achieved substantial success and demonstrated significant promise towards the quantitative and predictive modeling of IDPs and their dynamic interactions. We will also discuss important challenges remaining in the atomistic simulation of larger systems and how various coarse-grained approaches may help to bridge the remaining gaps in the accessible time- and length-scales of IDP simulations.

Modeling the Dynamics of Protein–Protein Interfaces, How and Why?

“…Despite advances in hardware technologies, the computational cost of simulating long time scales (multiple microseconds) to escape local energy minima can still present a limiting factor for many systems. These considerations led to the development of enhanced sampling strategies, focusing only on the interface sampling over time [ 50 ]. For example, Peiffenberger and Bates [ 51 ] used metadynamics [ 52 , 53 ] simulations within the contact map space (CMS).…”

“…This protein group is estimated to harbor around 25% of disease associated missense mutations [ 152 ], thus making IDPs/IDRs a central therapeutic target. As protein assemblies comprising IDPs or IDRs are very likely to form fuzzy complexes , where one or both partners in the interaction will retain some disorder [ 153 , 154 ], investigating the dynamics of such complexes appears to be an unavoidable step for understanding their function [ 50 , 155 ]. IDPs can also undergo folding-upon-binding transitions when assembling with another protein partner [ 156 ] (see Figure 2 b).…”

Toward Accurate Coarse-Grained Simulations of Disordered Proteins and Their Dynamic Interactions

“…The reason is that only averaged properties can be measured, which alone cannot resolve the heterogeneous ensemble and transient structural features. − There is thus an urgent need for molecular modeling and simulation to help provide these missing details. In particular, physics-based atomistic simulations can probe the conformational states and dynamics of proteins with high temporal and spatial resolutions. − A major limitation, however, for atomistic simulations of IDPs can be prohibitive in computational cost, especially for larger IDPs or for describing their dynamic interactions. This has motivated significant interest in developing coarse-grained (CG) models that can dramatically reduce the computational cost and extend the accessible length and timescales …”

“…In particular, physics-based atomistic simulations can probe the conformational states and dynamics of proteins with high temporal and spatial resolutions. − A major limitation, however, for atomistic simulations of IDPs can be prohibitive in computational cost, especially for larger IDPs or for describing their dynamic interactions. This has motivated significant interest in developing coarse-grained (CG) models that can dramatically reduce the computational cost and extend the accessible length and timescales …”

IDPConformerGenerator: A Flexible Software Suite for Sampling Conformational Space of Disordered Protein States

“…Disordered states of proteins, including unfolded states, intrinsically disordered regions (IDRs) of otherwise folded domains, as well as full intrinsically disordered proteins (IDPs) are increasingly recognized for the roles they play in folding kinetics 1 aggregation propensity 2,3 , critical biological functions 4 , and pathological disease states 5 . Structural insights are needed to better understand these disordered protein states, and a variety of solution experiments have been developed to enable structural and dynamic descriptions of disordered proteins using nuclear magnetic resonance (NMR), small angle X-ray scattering (SAXS), single molecule fluorescence (SMF) and other data types [6][7][8][9][10][11] . However, solution experimental data for disordered states are averaged over a very large number of heterogeneous interconverting conformations, leading to greater challenges in structural interpretation than for folded proteins.…”