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.