Mechanism of Ampicillin Hydrolysis by New Delhi Metallo-β-Lactamase 1 : Insight From QM/MM MP2 Calculation
© 2024 The Author(s). Journal of Computational Chemistry published by Wiley Periodicals LLC.
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 46(2024), 1 vom: 05. Jan., Seite e27544 |
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| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2025
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Journal Article MP2 NDM‐1 QM/MM catalytic mechanism kinetic isotope effect beta-Lactamases EC 3.5.2.6 Ampicillin 7C782967RD mehr... |
| Zusammenfassung: | © 2024 The Author(s). Journal of Computational Chemistry published by Wiley Periodicals LLC. 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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| Beschreibung: | Date Completed 05.12.2024 Date Revised 07.12.2024 published: Print Citation Status MEDLINE |
| ISSN: | 1096-987X |
| DOI: | 10.1002/jcc.27544 |