The combined quantum mechanics/molecular mechanics (QM/MM) simulations of equilibrium geometry configurations followed by electron density analysis provide reliable quantitative structure‐property relationship equations to estimate the reactivity of compounds in the active sites of enzymes. The main drawback is high computational cost of such calculations. Here, we report on a benchmark study aiming to optimize computational protocol for the accuracy of predictions. We considered an important example of cephalosporin hydrolysis in the active site of L1 metallo‐β‐lactamase and found that it is important to consider contributions to the one‐electron part of the QM Hamiltonian from all MM system rather than using the cutoff of electrostatic interactions. Switching from the reference PBE0‐D3/6‐31G(d,p) QM protocol to the reduced PBE0‐D3/6‐31G scheme decreases the number of basis set functions by almost twice, increasing the error of the rate constant estimates up to 18 seconds⁻¹ compared with the reference 10 seconds⁻¹. Therefore, the QM(PBE0‐D3/6‐31G)/MM(AMBER) level of theory can be recommended for estimates of cephalosporin reactivity in the search of new antibiotics.

中文翻译：

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L1金属β-内酰胺酶中头孢菌素氢键控制反应性的基准研究：高效可靠的QSPR方程

平衡几何构型的组合量子力学/分子力学（QM / MM）模拟，然后进行电子密度分析，提供了可靠的定量结构-性质关系方程，以估计化合物在酶活性位点的反应性。主要缺点是这种计算的高计算成本。在这里，我们报告了一项基准研究，旨在优化预测精度的计算协议。我们考虑了L1金属-β-内酰胺酶活性位点中头孢菌素水解的重要例子，发现重要的是考虑所有MM系统对QM哈密顿量的单电子部分的贡献，而不是使用静电相互作用的截止点。从参考PBE0-D3 / 6-31G（d，^-1与参考10秒^-1相比。因此，在寻找新抗生素时，可以建议使用QM（PBE0-D3 / 6-31G）/ MM（AMBER）理论水平来估计头孢菌素的反应性。