SOLVATION FREE-ENERGIES CALCULATED USING THE GB SA MODEL - SENSITIVITY OF RESULTS ON CHARGE SETS, PROTOCOLS, AND FORCE-FIELDS/

The sensitivity of aqueous solvation free energies (SFEs), estimated u sing 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 ch arge sets. Charges derived from electrostatic potential fitting to hig h level ab initio wave functions using the CHELPG procedure and ''clas s IV'' charges from AM1/CM1a or PM3/CM1p calculations yielded better r esults than the corresponding Mulliken charges. Calculated SFEs were s imilar to MC/FEP energies obtained in the presence of explicit TIP4P w ater. Further improvements were obtained by using GVB/6-31G* and MP2/ 6-31 + G* (CHELPG) charge sets that included correlation effects. SFE s calculated using charge sets assigned by the OPLSA force field gave the best results of all standard force fields (MM2, MM3*, MMFF, AMBE R, and OPLSA*) implemented in MacroModel. Comparison of relative and absolute SFEs computed using either the GB/SA continuum model or MC/FE P calculations in the presence of explicit TIP4P water showed that, in general, relative SFEs can be estimated with greater accuracy. A seco nd set of 20 mono-and difunctional molecules was also studied and rela tive SFEs estimated using energy minimization and thermodynamic cycle perturbation (TCP) protocols. SFEs calculated from TCP calculations us ing the GB/SA model were sensitive to bond lengths of dummy bonds (i.e ., bonds involving dummy atoms). In such cases, keeping the bond lengt hs of dummy bonds close to the corresponding bond lengths of the start ing structures improved the agreement of TCP-calculated SFEs with ener gy minimization results. Overall, these results indicate that GB/SA so lvation free energy estimates from simple energy minimization calculat ions are of similar accuracy and value to those obtained using more el aborate TCP protocols. (C) 1998 John Wiley & Sons, Inc.