Combined Metadynamics and Umbrella Sampling Method for the Calculation of Ion Permeation Free Energy Profiles

摘要

Free energy calculations are one of the most useful methods for the study of ion transport mechanisms through confined spaces such as protein ion channels. Their reliability depends on a correctly defined reaction coordinate (RC). A straight line is usually not a proper RC for such complicated processes, so in this work a combined metadynamics/umbrella sampling (MTD/US) method is proposed. In the combined method, the ion transport pathway is first identified by the MTD method, and then the free energy profile or potential of mean force (PMF) along the path is calculated using umbrella sampling. This combined method avoids the discontinuity problem often associated with normal umbrella sampling calculations that assume a straight line RC, and it provides a more physically accurate potential of mean force for such processes. The method is demonstrated for the proton transport process through the protein channel of aquaporin-1.