The treatment of solvation by a generalized Born model and a self-consistent charge-density functional theory-based...

We present a model to calculate the free energies of solvation of small organic compounds as well as large biomolecules. This model is based on a generalized Born (GB) model and a self-consistent charge-density functional theory-based tight-binding (SCC-DFTB) method with the nonelectrostatic contributions to the free energy of solvation modeled in terms of solvent-accessible surface areas (SA). The parametrization of the SCC-DFTB/GBSA model has been based on 60 neutral and six ionic molecules composed of H, C, N, O, and S, and spanning a wide range of chemical groups. Effective atomic radii as parameters have been obtained through Monte Carlo Simulated Annealing optimization in the parameter space to minimize the differences between the calculated and experimental free energies of solvation. The standard error in the free energies of solvation calculated by the final model is 1.11 kcal mol(-1). We also calculated the free energies of solvation for these molecules using a conductor-like screening model (COSMO) in combination with different levels of theory (AM1, SCC-DFTB, and B3LYP/6-31G*) and compared the results with SCC-DFTB/GBSA. To assess the efficiency of our model for large biomolecules, we calculated the free energy of solvation for a HIV protease-inhibitor complex containing 3,204 atoms using the SCC-DFTB/GBSA and the SCC-DFTB/COSMO models, separately. The computed relative free energies of solvation are comparable, while the SCC-DFTB/GBSA model is three to four times more efficient, in terms of computational cost.