Mechanism of Ampicillin Hydrolysis by New Delhi Metallo-β-Lactamase 1: Insight From QM/MM MP2 Calculation

IF 3.4 3区化学 Q2 CHEMISTRY, MULTIDISCIPLINARY

Journal of Computational Chemistry Pub Date : 2024-12-05 DOI:10.1002/jcc.27544

Rui Lai, Hui Li

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Abstract

The New Delhi metallo-β-lactamase 1 (NDM-1) can hydrolyze nearly all clinically important β-lactam antibiotics, narrowing the options for effective treatment of bacterial infections. QM/MM MP2 calculations are performed to reveal the mechanism of ampicillin hydrolysis catalyzed by NDM-1. It is found that the rate-determining step is the dissociation of hydrolyzed ampicillin from the NDM-1 active site, which requires a proton transfer from the bridging neutral water molecule to the newly formed carboxylate group. The precedent reaction steps, including the hydroxide nucleophilic addition, CN bond cleavage, and the protonation of the negative lactam N atom by a solvent water molecule, all require insignificant activation free energies. The calculated activation free energy for this rate-determining proton transfer step is 16.0 kcal/mol, in good agreement with experimental values of 13.7 ~ 14.7 kcal/mol. This proton transfer step exhibits a solvent hydrogen-deuterium kinetic isotope effect of 3.4, consistent with several experimental kinetic results.

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新德里金属-β-内酰胺酶1水解氨苄西林的机理：来自QM/MM MP2计算的见解

新德里金属β-内酰胺酶1 （NDM-1）可以水解几乎所有临床上重要的β-内酰胺类抗生素，缩小了有效治疗细菌感染的选择范围。通过QM/MM MP2计算揭示了NDM-1催化氨苄西林水解的机理。研究发现，速率决定步骤是水解氨苄西林与NDM-1活性位点的解离，这需要质子从桥接中性水分子转移到新形成的羧酸基上。之前的反应步骤，包括氢氧根亲核加成，C - γ - N键裂解，以及溶剂水分子对负内酰胺N原子的质子化，都需要微不足道的活化自由能。这一决定速率的质子转移步骤的活化能计算值为16.0 kcal/mol，与实验值13.7 ~ 14.7 kcal/mol吻合较好。该质子转移步骤表现出3.4的溶剂氢-氘动力学同位素效应，与几个实验动力学结果一致。

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来源期刊

Journal of Computational Chemistry 化学-化学综合

CiteScore

6.60

自引率

3.30%

发文量

247

审稿时长

1.7 months

期刊介绍： This distinguished journal publishes articles concerned with all aspects of computational chemistry: analytical, biological, inorganic, organic, physical, and materials. The Journal of Computational Chemistry presents original research, contemporary developments in theory and methodology, and state-of-the-art applications. Computational areas that are featured in the journal include ab initio and semiempirical quantum mechanics, density functional theory, molecular mechanics, molecular dynamics, statistical mechanics, cheminformatics, biomolecular structure prediction, molecular design, and bioinformatics.