A generalized Born/surface area (GB/SA) water model (Qiu, D.; Shenkin, P. S.; Hollinger, F. P.; Still, W. C. J. Phys. Chem. A 1997, 101, 3005−3014) in combination with the GROMOS96 force field is parametrized with the specific goal of application to protein simulations. The parameters are determined by a combined procedure of fitting to the free energies of solvation of amino acid-mimicking small molecules, rationally considering the effects of the solvent model on hydrogen-bond interactions, and most critically, carrying out long-time trial molecular dynamics simulations on two structurally distinct proteins, the B1 domain of streptococcal protein G and the bovine pancreatic trypsin inhibitor. The refined set of parameters is tested by carrying out a simulation on a third protein, the chymotrysin inhibitor 2. For all three proteins, we report separate 3 ns simulations using, respectively, the re-parametrized GB/SA model, the explicit solvent model, and another implicit solvent model which is mainly based...