Membrane proteins, due to their roles as cell receptors and signaling mediators, make prime candidates for drug targets. The computational analysis of protein ligand binding affinities has been widely employed as a tool in rational drug design efforts. Although efficient implicit solvent-based methods for modeling globular protein-ligand binding have been around for many years, the extension of such methods to membrane protein-ligand binding is still in its infancy. In this study, we extended the widely used Amber/MMPBSA method to model membrane protein-ligand systems, and we used it to analyze protein-ligand binding for the human purinergic platelet receptor (P2Y(12)R), a prominent drug target in the inhibition of platelet aggregation for the prevention of myocardial infarction and stroke. The binding affinities, computed by the Amber/MMPBSA method using standard parameters, correlate well with experiment. A detailed investigation of these parameters was conducted to assess their impact on the accuracy of the method. These analyses show the importance of properly treating the nonpolar solvation interactions and the electrostatic polarization in the binding of nucleotide agonists and non nucleotide antagonists to P2Y(12)R On the basis of the crystal structures and the experimental conditions in the binding assay, we further hypothesized that the nucleotide agonists lose their bound magnesium ion upon binding to P2Y(12)R, and our computational study supports this hypothesis. Ultimately, this work illustrates the value of computational analysis in the interpretation of experimental binding reactions.