Theoretical Studies on the Effects of Methods and Parameterization on the Calculated Free Energy of Hydration for Small Molecules

Free energies of hydration (FEH) have been computed for thirteen neutral and nine ionic species as a difference of theoretically calculated Gibbs free energies in solution and in the gas phase. In-solution calculations have been performed using both SCIPCM and PCM polarizable continuum models at the DFT/B3LYP and ab initio Hartree-Fock levels with two basis sets (6-31G* and 6-311++G**). Good linear correlation has been obtained for calculated and experimental gas-phase dipole moments, with an increase by about 30% upon solvation due to solute polarization. The geometry distortion in solution turns out to be small, whereas solute polarization energies are up to 3 kcal/mol for neutral molecules. Calculation of free energies of hydration with PCM provides a balanced set of values with 6-31G* and 6-311++G** basis sets for neutral molecules and ionic species, respectively. Explicit solvent calculations within Monte Carlo simulations applying free energy perturbation methods have been considered for twelve neutral molecules. Four different partial atomic charge sets have been studied, obtained by a fit to the gas-phase and in-solution molecular electrostatic potentials at in-solution optimized geometries. Calculated FEH values depend on the charge set and the atom model used. Results indicate a preference for the all-atom model and partial charges obtained by a fit to the molecular electrostatic potential of the solute computed at the SCIPCM/B3LYP/6-31G* level.