Calculation of solvation free energy from quantum mechanical charge density and continuum dielectric theory.

We have combined ultrasoft pseudopotential density functional theory utilizing plane wave basis with a Poisson-Boltzmann/solvent-accessible surface area (PB/SA) model to calculate the solvation free energy of small neutral organic compounds in water. The solute charge density obtained from density functional theory was directly used in solving the Poisson-Boltzmann equation to obtain the reaction field. The polarized electronic wave function of the solute in the solvent was solved by including the reaction field in the density functional Hamiltonian. The quantum mechanical and Poisson-Boltzmann equations were solved self-consistently until the charge density and reaction field converged. Using the solute charge density directly instead of a point-charge representation permitted asymmetric distortion and spreading out of the electron cloud. Because the electron density could leave the van der Waals surface to penetrate into the high-dielectric solvent, the reaction field generated by this density was generally smaller than that obtained by using the point-charge representation. In applying this model to calculate the solvation free energy of 31 small neutral organic molecules spanning a range of 25 kcal/mol, we obtained a root-mean-square error of only 1.3 kcal/mol if we allowed one adjustable parameter to shift the calculated solvation free energy.