Advances in the calculation of binding free energies

Abstract

In recent years, calculations of binding affinities from molecular simulations seem to have matured significantly. While the number of applications of such methods in drug design and biotechnology increases, the number of truly new methodological developments decreases. This review provides an overview of the current status of the field as reflected in recent publications. The focus is on the challenges that remain when using endstate, alchemical and pathway methods. For endstate methods this is the calculation of entropic contributions. For alchemical methods there are unsolved problems associated with the solvation of the active site, sampling slow degrees of freedom and when modifying the net charge. For pathway methods achieving sufficient sampling remains challenging. New trends are also highlighted, including the use of pathway methods for the quantification of protein-protein interactions.