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

TL;DR

This paper introduces a comprehensive MSM/RD framework that couples Markov state models with reaction-diffusion simulations, enabling large-scale, multi-particle modeling of protein interactions with verified benchmarks.

Contribution

It develops a general, mathematically grounded MSM/RD framework that extends to multiple particles and complex interactions, filling key gaps in current methods.

Findings

Successfully modeled protein-protein interactions at large scales.

Extended MSM/RD to multi-particle systems like pentameric rings.

Provided open-source software for reproducibility.

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 is lacking a multi-particle 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 parametrize 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.