Solvent models for protein-ligand binding: Comparison of implicit solvent Poisson and surface generalized born models with explicit solvent simulations

Solvent effects play a crucial role in mediating the interactions between p roteins and their ligands. Implicit solvent models offer some advantages fo r modeling these interactions, but they have not been parameterized 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 solv ation free energy calculations are more than 10(3) faster using the Surface Generalized Born implicit solvent model compared to FEP simulations with e xplicit solvent. For some of the electrostatic calculations needed to estim ate the binding free energy, there is near quantitative agreement between t he explicit and implicit solvent model results; overall, the qualitative tr ends in the binding predicted by the explicit solvent FEP simulations are r eproduced by the implicit solvent model. With an appropriate choice of refe rence system based on the binding of the discharged ligand, electrostatic i nteractions are found to enhance the binding affinity because the favorable Coulomb interaction energy between the ligand and protein more than compen sates for the unfavorable free energy cost of partially desolvating the lig and upon binding. Some of the effects of protein flexibility and thermal mo tions on charging the peptide in the solvated complex are also considered. (C) 2001 John Wiley & Sons, Inc.