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Membrane-bound protein receptors are a primary biological drug target, but the computational analysis of membrane proteins has been limited. In order to improve molecular mechanics Poisson–Boltzmann surface area (MMPBSA) binding free energy calculations for membrane protein–ligand systems, we have optimized a new heterogeneous dielectric implicit membrane model, with respect to free energy simulations in explicit membrane and explicit water, and implemented it into the Amber software suite. This new model supersedes our previous uniform, single dielectric implicit membrane model by allowing the dielectric constant to vary with depth within the membrane. We calculated MMPBSA binding free energies for the human purinergic platelet receptor (P2Y₁₂R) and two of the muscarinic acetylcholine receptors (M2R and M3R) bound to various antagonist ligands using both membrane models, and we …