Dynamic coarse-graining fills the gap between atomistic simulations and experimental investigations of mechanical unfolding

TL;DR

This paper introduces a dynamic coarse-graining method based on Markov state models that enables simulating biomolecular mechanical unfolding over experimentally relevant time scales while maintaining atomistic detail.

Contribution

The authors develop a novel MSM-based dynamic coarse-graining technique that bridges the gap between atomistic simulations and experimental unfolding timescales.

Findings

Achieves seven orders of magnitude in pulling speed simulation

Excellent agreement with fully atomistic simulations in rapid pulling regime

Determines unfolding rates from 10^{-8}/ns to 1/ns

Abstract

We present a dynamic coarse-graining technique that allows to simulate the mechanical unfolding of biomolecules or molecular complexes on experimentally relevant time scales. It is based on Markov state models (MSM), which we construct from molecular dynamics simulations using the pulling coordinate as an order parameter. We obtain a sequence of MSMs as a function of the discretized pulling coordinate, and the pulling process is modeled by switching among the MSMs according to the protocol applied to unfold the complex. This way we cover seven orders of magnitude in pulling speed. In the region of rapid pulling we additionally perform steered molecular dynamics simulations and find excellent agreement between the results of the fully atomistic and the dynamically coarse-grained simulations. Our technique allows the determination of the rates of mechanical unfolding in a dynamical range from approximately $10^{-8}$/ns to $1$/ns thus reaching experimentally accessible time regimes without abandoning atomistic resolution.