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Wepresent a quantum mechanics/molecular mechanics (QM/MM) methodto evaluate the partial charges of amino acid residues for use inMM potentials based on their protein environment. For each residueof interest, the nearby residues are included in the QM system whilethe rest of the protein is treated at the MM level of theory. Aftera short structural optimization, the partial charges of the centralresidue are fit to the electrostatic potential using the restrainedelectrostatic potential (RESP) method. The resulting charges and electrostaticpotential account for the individual environment of the residue, althoughthey lack the transferable nature of library partial charges. To evaluatethe quality of the QM/MM RESP charges, thermodynamic integration isused to measure the pKashift of the asparticacid residues in three different proteins, turkey egg lysozyme, beta-cryptogein,and Thioredoxin. Compared to the AMBER ff99SB library values, theQM/MM RESP charges show better agreement between the calculated andexperimental pKavalues for almost allof the residues considered. [ABSTRACT FROM AUTHOR]

Using the recently solved crystal structure of the human adenosine A2Areceptor, we applied MM/PBSA to compare the binding modes of caffeine with those of the high-affinity selective antagonist ZM241385. MD simulations were performed in the environment of the lipid membrane bilayer. Four low-energy binding modes of caffeine-A2Awere found, all of which had similar energies. Assuming an equal contribution of each binding mode of caffeine, the computed binding free energy difference between caffeine and ZM241385 is −2.4 kcal/mol, which compares favorably with the experimental value, −3.6 kcal/mol. The configurational entropy contribution of −0.9 kcal/mol from multiple binding modes of caffeine helps explain how a small molecule like caffeine can compete with a significantly larger molecule, ZM241385, which can form many more interactions with the receptor. We also performed residue-wise energy decomposition and found that Phe168, Leu249, and Ile274 contribute most significantly to the binding modes of caffeine and ZM241385. [ABSTRACT FROM AUTHOR]