In order to assign an energy contribution to the explicit-solvent effect, ∆∆G corr , we define it as the difference between the true solvation free energy of a compound in solution and the solvation free energy estimated based on a continuum model that neglects the effect. Taking the classical GNNIS model as a good representation of the true solvation free energy of a classically described molecule and the GB-Neck2 model as a continuum-based estimate, ∆∆G corr can then be approximated for the identically described molecule as,