Protein Folding and Ligand-Enzyme Binding from Bias-Exchange Metadynamics Simulations

Abstract

Bias-Exchange Metadynamics is a powerful technique that can be used for reconstructing the free energy and for enhancing the conformational search in complex biological systems. In this method, a large set of collective variables (CVs) is chosen and several metadynamics simulations are performed on different replicas of the system, each replica biasing a different CV. Exchanges between the bias potentials are periodically attempted according to a replica exchange scheme, and this process is repeated until convergence of the free energy profiles is obtained. Bias-Exchange Metadynamics has been used to understand several different biological phenomena. In particular, due to the efficaciously multidimensional nature of the bias, it is useful to study the folding process of small-to-medium size proteins, and ligandenzyme binding. This review intends to provide a comprehensive description of the algorithm and the approach used to analyze its output. We focus on the practical aspects that need to be addressed when one attempts to apply the method to study protein systems: choice of the appropriate set of parameters and CVs, proper treatment of boundary conditions, convergence criteria, and derivation of a thermodynamic and kinetic model of the system from the simulation results Keywords: Enhanced sampling, Free energy calculations, Protein folding, Ligand-enzyme binding, Bias-exchange metadynamics, Gaussians, Dihedral distance, Thermodynamic, weighted-histogram, Conformational Space