Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
Phys Chem Chem Phys. 2018 Dec 5;20(47):29637-29647. doi: 10.1039/c8cp05029e.
At a given pH, whether a metal-bound water molecule is deprotonated or not can be determined if the pKa of the metal-bound water molecule (denoted pKw) is known. Although protocols/tools to predict the protonation states of titratable amino acid residues and small molecules have been developed, an efficient and accurate method to predict the absolute pKw values of metal complexes is lacking. Here, we present calibrated methods for optimizing the geometries and computing the absolute pKw values of a wide range of Zn2+-complexes containing protein-like ligating groups. We tested 18 different geometry-optimization methods on 19 ultra high-resolution structures of Zn2+ complexes of varying coordination numbers and ligating atoms and 98 methods in reproducing 36 experimental pKw values of diverse Zn2+ complexes in the absence and presence of explicit water molecules. The results underscore the importance of estimating the Zn2+-bound water/hydroxide solvation properly, whereas correcting for the basis set superposition error was not found to be important. The protocol presented can be used to (i) evaluate the geometries of the different Zn2+-sites found in proteins and (ii) to dissect the individual contributions of the various factors modulating the pKw in Zn2+-sites found in proteins. Predicting absolute pKw values in various environments with efficiency and accuracy will indicate when a Zn2+-bound water molecule is deprotonated, thus providing physical insight into the mechanisms of enzyme-catalyzed reactions and the design of drug candidates that can displace a metal-bound water molecule.
在给定的 pH 值下，如果知道金属结合水分子的 pKa（表示为 pKw），就可以确定金属结合水分子是否发生去质子化。尽管已经开发出用于预测可质子化氨基酸残基和小分子质子化状态的协议/工具，但缺乏一种有效且准确的方法来预测金属配合物的绝对 pKw 值。在这里，我们提出了校准方法，用于优化广泛的含蛋白样配体的 Zn2+ 配合物的几何形状并计算其绝对 pKw 值。我们在 19 种不同配位数和配体原子的 Zn2+ 配合物的超高分辨率结构上测试了 18 种不同的几何优化方法，在没有和存在显式水分子的情况下，用 98 种方法重现了 36 种不同 Zn2+ 配合物的 36 个实验 pKw 值。结果强调了正确估计 Zn2+结合水分子/氢氧化物溶剂化的重要性，而校正基组叠加误差并不重要。所提出的方案可用于 (i) 评估蛋白质中不同 Zn2+ 结合位点的几何形状，(ii) 剖析调节蛋白质中 Zn2+ 结合位点 pKw 的各种因素的单独贡献。以效率和准确性预测各种环境中的绝对 pKw 值将指示 Zn2+ 结合水分子是否发生去质子化，从而为酶催化反应的机制和可以置换金属结合水分子的候选药物的设计提供物理见解。
