Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Phys Chem Chem Phys. 2018 Dec 5;20(47):29625-29636. doi: 10.1039/c8cp04776f.
Understanding when a metal-bound water molecule in a protein is deprotonated is important as this affects the charge distribution in the metal-binding/enzyme active site and thus their interactions, the enzyme mechanism, and inhibitor design. The protonation state of the metal-bound water molecule at a given pH depends on its pKa value, which in turn depends on the properties of the cation, its ligands, and the protein environment. Here, we reveal how and the extent to which (i) the first-shell composition (type, charge, and number of ligands), (ii) the metal site's immediate surroundings (first-shellsecond-shell hydrogen-bonding interactions, metal-ligand distance constraints, and ligand-binding mode) and (iii) the protein architecture and coupled solvent interactions (long-range electrostatic interactions and solvent exposure of the site) affect the Zn2+-bound water pKa. The results, which are consistent with available experimental pKa values of Zn2+-bound water, provide guidelines to predict when Zn2+-bound water would likely be deprotonated at physiological pH.
了解蛋白质中与金属配位的水分子何时去质子化非常重要，因为这会影响金属结合/酶活性部位的电荷分布，从而影响它们的相互作用、酶机制和抑制剂设计。在给定 pH 下，金属结合水分子的质子化状态取决于其 pKa 值，而 pKa 值又取决于阳离子的性质、其配体以及蛋白质环境。在这里，我们揭示了（i）第一壳层组成（配体的类型、电荷和数量）、（ii）金属位点的直接环境（第一壳层-第二壳层氢键相互作用、金属-配体距离约束和配体结合模式）以及（iii）蛋白质结构和耦合溶剂相互作用（远程静电相互作用和位点的溶剂暴露）如何以及在何种程度上影响 Zn2+-结合水的 pKa。这些结果与可用的 Zn2+-结合水的实验 pKa 值一致，为预测 Zn2+-结合水在生理 pH 下何时可能去质子化提供了指导。
