Kinetics from Metadynamics: Principles, Applications, and Outlook.

Abstract

Metadynamics is a popular enhanced sampling algorithm for computing the free energy landscape of rare events by using molecular dynamics simulation. Ten years ago, Tiwary and Parrinello introduced the infrequent metadynamics approach for calculating the kinetics of transitions across free energy barriers. Since then, metadynamics-based methods for obtaining rate constants have attracted significant attention in computational molecular science. Such methods have been applied to study a wide range of problems, including protein-ligand binding, protein folding, conformational transitions, chemical reactions, catalysis, and nucleation. Here, we review the principles of elucidating kinetics from metadynamics-like approaches, subsequent methodological developments in this area, and successful applications on chemical, biological, and material systems. We also highlight the challenges of reconstructing accurate kinetics from enhanced sampling simulations and the scope of future developments.