Estimation of Absolute Free Energies of Hydration Using Continuum Methods:  Accuracy of Partial Charge Models and...

Absolute free energies of hydration (ΔGhyd) for more than 500 neutral and charged compounds have been computed, using Poisson-Boltzmann (PB) and Generalized Born (GB) continuum methods plus a solvent-accessible surface area (SA) term, to evaluate the accuracy of eight simple point-charge models used in molecular modeling. The goal is to develop improved procedures and protocols for protein-ligand binding calculations and virtual screening (docking). The best overall PBSA and GBSA results, in comparison with experimental ΔGhyd values for small molecules, were obtained using MSK, RESP, or ChelpG charges obtained from ab initio calculations using 6-31G* wave functions. Correlations using semiempirical (AM1BCC, AM1CM2, and PM3CM2) or empirical (Gasteiger-Marsili and MMFF94) methods yielded mixed results, particularly for charged compounds. For neutral compounds, the AM1BCC method yielded the best agreement with experimental results. In all cases, the PBSA and GBSA results are highly correlated (overall r(2) = 0.94), which highlights the fact that various partial charge models influence the final results much more than which continuum method is used to compute hydration free energies. Overall improved agreement with experimental results was demonstrated using atom-based constants in place of a single surface area term. Sets of optimized SA constants, suitable for use with a given charge model, were derived by fitting to the difference in experimental free energies and polar continuum results. The use of optimized atom-based SA constants for the computation of ΔGhyd can fine-tune already reasonable agreement with experimental results, ameliorate gross deficiencies in any particular charge model, account for nonoptimal radii, or correct for systematic errors.