The Use of Anisotropic Potentials in Modeling Water and Free Energies of Hydration

We propose a novel, anisotropic rigid-body intermolecular potential model to predict the properties of water and the hydration free energies of neutral organic solutes. The electrostatic interactions of water and the solutes are modeled using atomic multipole moments up to hexadecapole; these are obtained from distributed multipole analysis of the quantum mechanically computed charge densities and include average polarization effects in solution. The repulsion-dispersion water-water interactions are modeled with a three-site, exp-6 model fitted to the experimental liquid water density and oxygen-oxygen radial distribution function at ambient conditions. The proposed water model reproduces well several water properties not used in its parametrization, including vapor-liquid coexistence densities, the maximum in liquid water density at atmospheric pressure, the structure of ordered ice polymorphs, and the liquid water heat capacity. The model is used to compute the hydration free energy of 10 neutral organic solutes using explicit-solvent free energy perturbation. The solute-solute repulsion-dispersion intermolecular potential is obtained from previous parametrizations on organic crystal structures. In order to calculate the free energies of hydration, water-solute repulsion-dispersion interactions are modeled using Lorenz-Berthelot combining rules. The root-mean-square error of the predicted hydration free energies is 1.5 kcal mol-1, which is comparable to the error found using a continuum mean-field quantum mechanical approach parametrized using experimental free energy of hydration data. The results are also contrasted with explicit-solvent hydration free energies obtained with an atomic charge representation of the solute's charge density computed at the same level of theory used to compute the distributed multipoles. Replacing the multipole description of the solute's charge density with an atomic charge model changes the free energy of hydration by as much as 3 kcal mol-1 and provides an estimate for the effect of the modeling quality of the intermolecular electrostatic forces in free energy of solvation calculations