Abstract
Fast and accurate calculation of solvation free energies is central to many applications, such as rational drug design. In this study, we present a grid-based molecular surface implementation of "R6" flavor of the generalized Born (GB) implicit solvent model, named GBNSR6. The speed, accuracy relative to numerical Poisson-Boltzmann treatment, and sensitivity to grid surface parameters are tested on a set of 15 small protein-ligand complexes and a set of biomolecules in the range of 268 to 25099 atoms. Our results demonstrate that the proposed model provides a relatively successful compromise between the speed and accuracy of computing polar components of the solvation free energies (ΔG(pol)) and binding free energies (ΔΔG(pol)). The model tolerates a relatively coarse grid size h = 0.5 Å, where the grid artifact error in computing ΔΔG(pol) remains in the range of k(B)T ∼ 0.6 kcal/mol. The estimated ΔΔG(pol)s are well correlated (r(2) = 0.97) with the numerical Poisson-Boltzmann reference, while showing virtually no systematic bias and RMSE = 1.43 kcal/mol. The grid-based GBNSR6 model is available in Amber (AmberTools) package of molecular simulation programs.