基于参考势的从头算量子力学/分子力学混合方法研究Parvalbumin B蛋白结合钙、镁离子的选择性

蛋白的离子选择性与蛋白的功能密切相关，而离子选择性本质上来源于蛋白分子与离子结合自由能的差别. 尽管近几十年来分子力场在描述蛋白体系相互作用方面取得了长足的进步，由于缺乏对静电极化和电荷转移效应显式的描述，传统的分子力场依然难以精确地描述金属蛋白体系中蛋白质与金属离子的相互作用. 量子化学方法非常适合于蛋白质与金属离子之间相互作用的描述. 但是在分子模拟中采用量子化学方法则太昂贵了. 近年来发展起来的参考势方法在保证计算精度的前提下兼顾效率，可以有效地解决这个窘境. 在这个方法中，动力学模拟的轨迹是在分子力场的精度下获得的. 随后，通过从分子力场到量子化学方法的矫正，从而获得在量子化学势函数级别下的自由能信息. 本文采用参考势函数方法研究了Parvalbumin B蛋白的结合口袋对钙、镁离子的选择性. 计算结果表明电荷转移效应非常重要，而量子化学方法可以比较精确地预测离子的选择性. 并且，量子化学区域的选择对于结果的可靠性也是非常重要的.

Selectivity of Parvalbumin B Protein Binding to Ca2+ and Mg2+ at an Ab Initio QM/MM Level Using the Reference-Potential Method

Ion selectivity in protein binding sites is of great significance to biological functions. Although additive force fields have been successfully applied to various protein-related studies, it is difficult to well capture the subtle metal-protein interaction for the prediction of ion selectivity, due to the remarkable polarization and charge transfer effect between the metals and the surrounding residues. Quantum mechanics-based methods are well-suited for dealing with these systems, but they are too costly to apply in a direct manner. In this work, the reference-potential method (RPM) was used to measure the selectivity for calcium and magnesium cations in the binding pocket of parvalbumin B protein by calculating the free energy change associated with this substitution reaction at an ab initio quantum mechanics/molecular mechanics (QM/MM) level. The alchemical transformations were performed at the molecular mechanics level, and the relative binding free energy was then corrected to the QM/MM level via thermodynamic perturbation. In this way, the free energy change at the QM/MM level for the substitution reaction was obtained without running the QM/MM simulations, thus remarkably enhancing the efficiency. In the reweighting process, we found that the selection of the QM region greatly affects the accuracy of the QM/MM method. In particular, the charge transfer effect on the free energy change of a reaction cannot be neglected.