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Factors Governing the Bridging Water Protonation State in Polynuclear Mg(2+) Proteins.

An aqua ligand bridges metal cations in a wide variety of enzymes, many of which are drug targets for various diseases. However, the factors affecting its protonation state and thus biological roles remain elusive. By computing the free energy for replacing the bridging H2O by OH(-) in various model Mg(2+) sites, we have evaluated how the nature of an aqua bridge depends on the site's net charge (i.e., the number of charged ligands in the first and second shell and the number of metal cations), the site's solvent exposure, the ligand's charge-donating ability, the bridging oxygen's hydrogen-bonding interactions, intramolecular proton transfer from the bridging H2O to a nearby carboxylate, and the metal coordination number. The results reveal the key factors dictating the protonation state of bridging H2O and provide guidelines in predicting whether H2O or OH(-) bridges two Mg(2+) in polynuclear sites. This helps to elucidate the nucleophile in the enzyme-catalyzed reaction and the net charge of the metal complex (metal cation and first-shell ligands), which plays a critical role in binding.