Enhanced Conformational Sampling using Replica Exchange with Collective-Variable Tempering

TL;DR

This paper introduces a novel enhanced sampling method combining metadynamics with replica exchange, significantly improving conformational sampling efficiency in molecular dynamics simulations of RNA and proteins.

Contribution

The authors develop a flexible, adaptive biasing technique that integrates well-tempered metadynamics into a Hamiltonian replica-exchange framework, enabling better sampling of complex conformational landscapes.

Findings

Reduced free-energy barriers for collective variables

Effective sampling of alanine dipeptide conformations

Successful application to tetranucleotide folding

Abstract

The computational study of conformational transitions in RNA and proteins with atomistic molecular dynamics often requires suitable enhanced sampling techniques. We here introduce a novel method where concurrent metadynamics are integrated in a Hamiltonian replica-exchange scheme. The ladder of replicas is built with different strength of the bias potential exploiting the tunability of well-tempered metadynamics. Using this method, free-energy barriers of individual collective variables are significantly reduced compared with simple force-field scaling. The introduced methodology is flexible and allows adaptive bias potentials to be self-consistently constructed for a large number of simple collective variables, such as distances and dihedral angles. The method is tested on alanine dipeptide and applied to the difficult problem of conformational sampling in a tetranucleotide.