Molecular dynamics simulations of the mononuclear zinc-β-lactamase from Bacillus cereus complexed with benzylpenicillin and a quantum chemical study of the reaction mechanism
Molecular dynamics simulations of the mononuclear zinc-β-lactamase from Bacillus cereus complexed with benzylpenicillin and a quantum chemical study of the reaction mechanism
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DOI：
10.1021/ja0113246
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发表时间：
2001-10-10
影响因子：
15
通讯作者：
Merz, KM
中科院分区：
文献类型：
--
作者：
Díaz, N;Suárez, D;Merz, KM
在此，我们介绍了对蜡样芽胞杆菌锌-β-内酰胺酶和青霉素之间形成的米氏复合体进行MD模拟的结果。讨论了底物结合引起的结构和动力学效应，保守残基的具体作用，以及米氏络合物的近攻击构象。用量子化学方法(HF/6-31G*和B3LYP/6-31G*)研究了组氨酸残基(His86、His88和His149)的侧链与锌的络合反应以及Asp90和His210的侧链组成的单锌体系催化N-甲基吡啶酮的水解反应。从这个模型系统中，我们建立了对接到活性中心的预活性络合物和过渡态构型的分子力学表示。然后对这些静态模型进行了线性标度半经验计算和连续介质溶剂模型的耦合。我们认为蜡状芽孢杆菌酶的实验速率数据与His210作为质子供体的β-内酰胺底物的一步水解机制是兼容的。
Herein, we present results from MD simulations of the Michaelis complex formed between the B. cereus zinc-beta -lactamase enzyme and benzylpenicillin. The structural and dynamical effects induced by substrate-binding, the specific role of the conserved residues, and the near attack conformers of the Michaelis complex are discussed. Quantum chemical methods (HF/6-31G* and B3LYP/6-31G*) are also applied to study the hydrolysis reaction of N-methylazetidinone catalyzed by a monozinc system consisting of the side chains of the histidine residues (His86, His88, and His149) complexed with Zn-OH and the side chains of Asp90 and His210. From this model system, we built molecular-mechanics representations of the prereactive complex and transition state configurations docked into the active site. Linear-scaling semiempirical calculations coupled with a continuum solvent model were then performed on these static models. We propose that the experimental rate data for the B. cereus enzyme is compatible with a one-step mechanism for the hydrolysis of beta -lactam substrates in which His210 acts as a proton donor.