MOLECULAR-DYNAMICS FREE-ENERGY PERTURBATION CALCULATIONS - INFLUENCE OF NONBONDED PARAMETERS ON THE FREE-ENERGY OF HYDRATION OF CHARGED ANDNEUTRAL 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 para meters, together with point charge models obtained from Mulliken popul ation analysis and from ab initio 6-31G(*) molecular electrostatic po tentials. The variation in absolute free energy found for methane with the two sets of charges suggests that, as expected, the role of the e lectrostatic term is minor in comparison with the sampling imperfectio ns of the simulation. The case study of methanol illustrates the diffi culties in deriving an unambiguously ''correct'' charge model that are often encountered when calculating the absolute free energy of hydrat ion of flexible molecules. Fortuitously, it appears that, whether Mull iken or electrostatic potential derived charges are employed and wheth er the molecule is constrained to a rigid low-energy conformation or n ot, no major difference in free energy is observed. Concerning the amm onium ion, the generally overestimated magnitude of the electrostatic contribution to the total free energy of hydration when a Born-type co rrection is included confirms the limitations of a standard two-body a dditive model for simulating absolute solvation free energies of charg ed solutes.