Multiscale molecular kinetics by coupling Markov state models and reaction-diffusion dynamics.

Abstract

A novel approach to simulate simple protein-ligand systems at large time and length scales is to couple Markov state models (MSMs) of molecular kinetics with particle-based reaction-diffusion (RD) simulations, MSM/RD. Currently, MSM/RD lacks a mathematical framework to derive coupling schemes, is limited to isotropic ligands in a single conformational state, and lacks multiparticle extensions. In this work, we address these needs by developing a general MSM/RD framework by coarse-graining molecular dynamics into hybrid switching diffusion processes. Given enough data to parameterize the model, it is capable of modeling protein-protein interactions over large time and length scales, and it can be extended to handle multiple molecules. We derive the MSM/RD framework, and we implement and verify it for two protein-protein benchmark systems and one multiparticle implementation to model the formation of pentameric ring molecules. To enable reproducibility, we have published our code in the MSM/RD software package.