Statistical Mechanics of Ligand-Receptor Noncovalent Association, Revisited: Binding Site and Standard State Volumes in Modern Alchemical Theories

The present paper is intended to be a comprehensive assessment and rationalization, from a statistical mechanics perspective, of existing alchemical theories for binding free energy calculations of ligand-receptor systems. In detail, the statistical mechanics foundation of noncovalent interactions in ligand-receptor systems is revisited, providing a unifying treatment that encompasses the most important variants in the alchemical approaches from the seminal double annihilation method [Jorgensen et al. J. Chem. Phys. 1988; 89, 3742] to the double decoupling method [Gilson et al. Biophys. J. 1997; 72, 1047] and the Deng and Roux alchemical theory [Deng and Roux J. Chem. Theory Comput. 2006; 2, 1255]. Connections and differences between the various alchemical approaches are highlighted and discussed.