Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
J Chem Theory Comput. 2020 May 12;16(5):3121-3134. doi: 10.1021/acs.jctc.0c00153. Epub 2020 Apr 16.
Quantum-mechanical/molecular-mechanical (QM/MM) methods are essential to the study of metalloproteins, but the relative importance of sampling and degree of QM treatment in achieving quantitative predictions is poorly understood. We study the relative magnitude of configurational and QM-region sensitivity of energetic and electronic properties in a representative Zn metal binding site of a DNA methyltransferase. To quantify property variations, we analyze snapshots extracted from 250 ns of molecular dynamics simulation. To understand the degree of QM-region sensitivity, we perform analysis using QM regions ranging from a minimal 49-atom region consisting only of the Zn metal and its four coordinating Cys residues up to a 628-atom QM region that includes residues within 12 Å of the metal center. Over the configurations sampled, we observe that illustrative properties (e.g., rigid Zn removal energy) exhibit large fluctuations that are well captured with even minimal QM regions. Nevertheless, for both energetic and electronic properties, we observe a slow approach to asymptotic limits with similarly large changes in absolute values that converge only with larger (ca. 300-atom) QM region sizes. For the smaller QM regions, the electronic description of Zn binding is incomplete: the metal binds too tightly and is too stabilized by the strong electrostatic potential of MM point charges, and the Zn-S bond covalency is overestimated. Overall, this work suggests that efficient sampling with QM/MM in small QM regions is an effective method to explore the influence of enzyme structure on target properties. At the same time, accurate descriptions of electronic and energetic properties require a larger QM region than the minimal metal-coordinating residues in order to converge treatment of both metal-local bonding and the overall electrostatic environment.
量子力学/分子力学 (QM/MM) 方法对于研究金属蛋白至关重要，但对于实现定量预测采样的相对重要性和 QM 处理的程度理解甚少。我们研究了在 DNA 甲基转移酶的代表性 Zn 金属结合位点中，能量和电子性质的构象和 QM 区域敏感性的相对大小。为了量化性质变化，我们分析了从 250ns 分子动力学模拟中提取的快照。为了理解 QM 区域敏感性的程度，我们使用 QM 区域进行分析，QM 区域范围从仅包含 Zn 金属及其四个配位 Cys 残基的最小 49 原子区域到包含距金属中心 12Å 内残基的 628 原子 QM 区域。在所采样的构型中，我们观察到说明性性质（例如，刚性 Zn 去除能）表现出很大的波动，即使使用最小的 QM 区域也能很好地捕捉到这些波动。然而，对于能量和电子性质，我们观察到渐近极限的缓慢逼近，绝对值也有很大的变化，只有更大的（约 300 原子）QM 区域尺寸才能收敛。对于较小的 QM 区域，Zn 结合的电子描述是不完整的：金属结合得太紧，MM 点电荷的强静电势使其太稳定，并且 Zn-S 键的共价性被高估。总体而言，这项工作表明，在较小的 QM 区域中使用 QM/MM 进行有效的采样是一种探索酶结构对目标性质影响的有效方法。同时，为了收敛金属局部键合和整体静电环境的处理，准确描述电子和能量性质需要比最小的金属配位残基更大的 QM 区域。
