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
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, CN 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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来源期刊
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.
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