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| - Binding Free Energy Contributions of Interfacial Waters inHIV-1 Protease/Inhibitor Complexes
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| - Water molecules are commonly observed in crystal structures of protein−ligand complexes wherethey mediate protein−ligand binding. It is of considerable theoretical and practical importance to determinequantitatively the individual free energy contributions of these interfacial water molecules to protein−ligandbinding and to elucidate factors that influence them. The double-decoupling free energy molecular dynamicssimulation method has been used to calculate the binding free energy contribution for each of the fourinterfacial water molecules observed in the crystal structure of HIV-1 protease complexed with KNI-272, apotent inhibitor. While two of these water molecules contribute significantly to the binding free energy, theother two have close to zero contribution. It was further observed that the protonation states of two catalyticaspartate residues, Asp25 and Asp125, strongly influence the free energy contribution of a conservedwater molecule Wat301 and that different inhibitors significantly influence the free energy contribution ofWat301. Our results have important implications on our understanding of the role of interfacial watermolecules in protein−ligand binding and to structure-based drug design aimed at incorporating theseinterfacial water molecules into ligands.
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