Flow-dependent unfolding and refolding of an RNA by nonequilibrium umbrella sampling

TL;DR

This paper introduces a parallel nonequilibrium umbrella sampling method to study rare unfolding and refolding events in RNA molecules under flow, revealing detailed pathways and kinetics that are difficult to observe with standard techniques.

Contribution

The authors develop and apply a parallel NEUS method for simulating RNA unfolding under flow, enabling observation of rare events and detailed pathway analysis in nonequilibrium conditions.

Findings

Observed unfolding events with mean first passage times up to 1.4 seconds.

Identified two competing unfolding pathways involving different intramolecular contacts.

Demonstrated the effectiveness of NEUS in exploring rare, slow transitions in biomolecular systems.

Abstract

Nonequilibrium experiments of single biomolecules such as force-induced unfolding reveal details about a few degrees of freedom of a complex system. Molecular dynamics simulations can provide complementary information, but exploration of the space of possible configurations is often hindered by large barriers in phase space that separate metastable regions. To solve this problem, enhanced sampling methods have been developed that divide a phase space into regions and integrate trajectory segments in each region. These methods boost the probability of passage over barriers, and facilitate parallelization since integration of the trajectory segments does not require communication, aside from their initialization and termination. Here we present a parallel version of an enhanced sampling method suitable for systems driven far from equilibrium: nonequilibrium umbrella sampling (NEUS). We apply this method to a coarse-grained model of a 262-nucleotide RNA molecule that unfolds and refolds in an explicit flow field modeled with stochastic rotation dynamics. Using NEUS we are able to observe extremely rare unfolding events that have mean first passage times as long as 1.4 s (3.4 E13 dynamics steps). We examine the unfolding process for a range of flow rates of the medium, and we describe two competing pathways in which different intramolecular contacts are broken.