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.