Solvent effects play a crucial role in mediating the interactions between proteins and their ligands. Implicit solvent models offer some advantages for modeling these interactions but they have not been parametrized on such complex problems, and therefore it is not clear how reliable they are. We have studied the binding of an octapeptide ligand to the murine MHC class I protein using both explicit solvent and implicit solvent models. The solvation free energy calculations are more than103faster using the Surface Generalized Born implicit solvent model as compared to FEP simulations with explicit solvent. For some of the electrostatic calculations needed to estimate the binding free energy, there is near quantitative agreement between the explicit and implicit solvent model results; overall the qualitative trends in the binding predicted by the explicit solvent FEP simulations are reproduced by the implicit solvent model. With an appropriate choice of reference system based on the binding of the discharged ligand, electrostatic interactions are found to enhance the binding affinity because the favorable Coulomb interaction energy between the ligand and protein more than compensates for the unfavorable free energy cost of partially desolvating the ligand upon binding. Some of the effects of protein flexibility and thermal motions on charging the peptide in the solvated complex are also considered. ©2000 American Institute of Physics.