MOLECULAR-DYNAMICS FREE-ENERGY PERTURBATION CALCULATIONS - INFLUENCE OF NONBONDED PARAMETERS ON THE FREE-ENERGY OF HYDRATION OF CHARGED AND NEUTRAL SPECIES

The absolute free energies of hydration of methane, methanol, and the ammonium ion have been determined from free energy perturbation (FEP) calculations, using two different sets of nonbonded van der Waals parameters, together with point charge models obtained from Mulliken population analysis and from ab initio 6-31G(**) molecular electrostatic potentials. The variation in absolute free energy found for methane with the two sets of charges suggests that, as expected, the role of the electrostatic term is minor in comparison with the sampling imperfections of the simulation. The case study of methanol illustrates the difficulties in deriving an unambiguously ''correct'' charge model that are often encountered when calculating the absolute free energy of hydration of flexible molecules. Fortuitously, it appears that, whether Mulliken or electrostatic potential derived charges are employed and whether the molecule is constrained to a rigid low-energy conformation or not, no major difference in free energy is observed. Concerning the ammonium ion, the generally overestimated magnitude of the electrostatic contribution to the total free energy of hydration when a Born-type correction is included confirms the limitations of a standard two-body additive model for simulating absolute solvation free energies of charged solutes.