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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. 

Abstract Efficient sampling of the conformational space is essential for quantitative simulations of proteins. The multiscale enhanced sampling (MSES) method accelerates atomistic sampling by coupling it to a coarse‐grained (CG) simulation. Bias from coupling to the CG model is removed using Hamiltonian replica exchange, such that one could benefit simultaneously from the high accuracy of atomistic models and fast dynamics of CG ones. Here, we extend MSES to allow independent control of the effective temperatures of atomistic and CG simulations, by directly scaling the atomistic and CG Hamiltonians. The new algorithm, named MSES with independent tempering (MSES‐IT), supports more sophisticated Hamiltonian and temperature replica exchange protocols to further improve the sampling efficiency. Using a small but nontrivial β‐hairpin, we show that setting the effective temperature of CG model in all conditions to its melting temperature maximizes structural transition rates at the CG level and promotes more efficient replica exchange and diffusion in the condition space. As the result, MSES‐IT drive faster reversible transitions at the atomic level and leads to significant improvement in generating converged conformational ensembles compared to the original MSES scheme. 

The generalized Born with molecular volume and solvent accessible surface area (GBMV2/SA) implicit solvent model provides an accurate description of molecular volume and has the potential to accurately describe the conformational equilibria of structured and disordered proteins. However, its broader application has been limited by the computational cost and poor scaling in parallel computing. Here, we report an efficient implementation of both the electrostatic and nonpolar components of GBMV2/SA on graphics processing unit (GPU) within the CHARMM/OpenMM module. The GPU‐GBMV2/SA is numerically equivalent to the original CPU‐GBMV2/SA. The GPU acceleration offers ~60‐ to 70‐fold speedup on a single NVIDIA TITAN X (Pascal) graphics card for molecular dynamic simulations of both folded and unstructured proteins of various sizes. The current implementation can be further optimized to achieve even greater acceleration with minimal reduction on the numerical accuracy. The successful development of GPU‐GBMV2/SA greatly facilitates its application to biomolecular simulations and paves the way for further development of the implicit solvent methodology. © 2019 Wiley Periodicals, Inc.