Solvation free energies calculated using the GB/SA model: Sensitivity of results on charge sets, protocols, and force fields

Abstract

The sensitivity of aqueous solvation free energies (SFEs), estimated using the GB/SA continuum solvent model, on charge sets, protocols, and force fields, was studied. Simple energy calculations using the GB/SA solvent model were performed on 11 monofunctional organic compounds. Results indicate that calculated SFEs are strongly dependent on the charge sets. Charges derived from electrostatic potential fitting to high level ab initio wave functions using the CHELPG procedure and “class IV” charges from AM1/CM1a or PM3/CM1p calculations yielded better results than the corresponding Mulliken charges. Calculated SFEs were similar to MC/FEP energies obtained in the presence of explicit TIP4P water. Further improvements were obtained by using GVB/6-31G** and MP2/6-31+G** (CHELPG) charge sets that included correlation effects. SFEs calculated using charge sets assigned by the OPLSA* force field gave the best results of all standard force fields (MM2*, MM3*, MMFF, AMBER*, and OPLSA*) implemented in MacroModel. Comparison of relative and absolute SFEs computed using either the GB/SA continuum model or MC/FEP calculations in the presence of explicit TIP4P water showed that, in general, relative SFEs can be estimated with greater accuracy. A second set of 20 mono- and difunctional molecules was also studied and relative SFEs estimated using energy minimization and thermodynamic cycle perturbation (TCP) protocols. SFEs calculated from TCP calculations using the GB/SA model were sensitive to bond lengths of dummy bonds (i.e., bonds involving dummy atoms). In such cases, keeping the bond lengths of dummy bonds close to the corresponding bond lengths of the starting structures improved the agreement of TCP-calculated SFEs with energy minimization results. Overall, these results indicate that GB/SA solvation free energy estimates from simple energy minimization calculations are of similar accuracy and value to those obtained using more elaborate TCP protocols. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 769–780, 1998