Frequency adaptive metadynamics for the calculation of rare-event kinetics

TL;DR

This paper introduces a frequency-adaptive metadynamics method that enhances the accuracy and efficiency of calculating rare-event kinetics in biomolecular systems, overcoming limitations of existing approaches for slow processes.

Contribution

The authors develop a novel frequency-adaptive strategy that combines normal and infrequent metadynamics to improve rate calculations for slow kinetic processes.

Findings

Improves precision and accuracy of rate calculations

Extends applicability to slower kinetic processes

Reduces computational cost for kinetic predictions

Abstract

The ability to predict accurate thermodynamic and kinetic properties in biomolecular systems is of both scientific and practical utility. While both remain very difficult, predictions of kinetics are particularly difficult because rates, in contrast to free energies, depend on the route taken and are thus not amenable to all enhanced sampling methods. It has recently been demonstrated that it is possible to recover kinetics through so called `infrequent metadynamics' simulations, where the simulations are biased in a way that minimally corrupts the dynamics of moving between metastable states. This method, however, requires the bias to be added slowly, thus hampering applications to processes with only modest separations of timescales. Here we present a frequency-adaptive strategy which bridges normal and infrequent metadynamics. We show that this strategy can improve the precision and accuracy of rate calculations at fixed computational cost, and should be able to extend rate calculations for much slower kinetic processes.