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Molecular mechanism of nitrocefin hydrolysis by the L1 metallo-β-lactamase: a benchmark study.

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Title: Molecular mechanism of nitrocefin hydrolysis by the L1 metallo-β-lactamase: a benchmark study.
Authors: Krivitskaya, Alexandra V.1 (AUTHOR), Polyakov, Igor V.2,3 (AUTHOR), Khrenova, Maria G.1,2,3 (AUTHOR) khrenovamg@my.msu.ru
Source: Molecular Physics. Feb2026, Vol. 124 Issue 3/4, p1-9. 9p.
Subjects: Beta lactamases, Density functionals, Gibbs' energy diagram, Electron density, Beta lactam antibiotics, Biocatalysis, Molecular dynamics
Abstract: Nitrocefin hydrolysis by metallo-β-lactamase is an important model chemical reaction mimicking cephalosporin antibiotic inactivation. Due to the specific chromogenic properties of the nitrocefin, transient kinetic data for this reaction is available. Despite its importance in the understanding of the reaction mechanism, these data can be utilised to verify benchmark calculations. This reaction is complicated from the computational viewpoint as the active site carries two double charged cations and therefore is highly polarised; nucleophilic attack and formation of the electrophilic site should be properly described. We calculate Gibbs-free energy profiles of three chemical steps comprising the entire reaction at the QM(DFT)/MM molecular dynamics level. We compare results obtained with three hybrid functionals differing in the contribution of the exact Hartree–Fock exchange, B3LYP-D3, PBE0-D3 and BHHLYP-D3. Among them, only calculations performed at the QM(PBE0-D3)/MM level were able to properly describe the intermediate accumulation and the limiting step. Laplacian of electron density maps clarify the influence of the computational protocol on the electrophilic site formation and covalent bond polarisation. [ABSTRACT FROM AUTHOR]
Copyright of Molecular Physics is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Molecular mechanism of nitrocefin hydrolysis by the L1 metallo-β-lactamase: a benchmark study.
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  Data: <searchLink fieldCode="AR" term="%22Krivitskaya%2C+Alexandra+V%2E%22">Krivitskaya, Alexandra V.</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Polyakov%2C+Igor+V%2E%22">Polyakov, Igor V.</searchLink><relatesTo>2,3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Khrenova%2C+Maria+G%2E%22">Khrenova, Maria G.</searchLink><relatesTo>1,2,3</relatesTo> (AUTHOR)<i> khrenovamg@my.msu.ru</i>
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  Data: <searchLink fieldCode="JN" term="%22Molecular+Physics%22">Molecular Physics</searchLink>. Feb2026, Vol. 124 Issue 3/4, p1-9. 9p.
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  Data: <searchLink fieldCode="DE" term="%22Beta+lactamases%22">Beta lactamases</searchLink><br /><searchLink fieldCode="DE" term="%22Density+functionals%22">Density functionals</searchLink><br /><searchLink fieldCode="DE" term="%22Gibbs'+energy+diagram%22">Gibbs' energy diagram</searchLink><br /><searchLink fieldCode="DE" term="%22Electron+density%22">Electron density</searchLink><br /><searchLink fieldCode="DE" term="%22Beta+lactam+antibiotics%22">Beta lactam antibiotics</searchLink><br /><searchLink fieldCode="DE" term="%22Biocatalysis%22">Biocatalysis</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink>
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  Data: Nitrocefin hydrolysis by metallo-β-lactamase is an important model chemical reaction mimicking cephalosporin antibiotic inactivation. Due to the specific chromogenic properties of the nitrocefin, transient kinetic data for this reaction is available. Despite its importance in the understanding of the reaction mechanism, these data can be utilised to verify benchmark calculations. This reaction is complicated from the computational viewpoint as the active site carries two double charged cations and therefore is highly polarised; nucleophilic attack and formation of the electrophilic site should be properly described. We calculate Gibbs-free energy profiles of three chemical steps comprising the entire reaction at the QM(DFT)/MM molecular dynamics level. We compare results obtained with three hybrid functionals differing in the contribution of the exact Hartree–Fock exchange, B3LYP-D3, PBE0-D3 and BHHLYP-D3. Among them, only calculations performed at the QM(PBE0-D3)/MM level were able to properly describe the intermediate accumulation and the limiting step. Laplacian of electron density maps clarify the influence of the computational protocol on the electrophilic site formation and covalent bond polarisation. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Molecular Physics is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1080/00268976.2025.2456688
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      – Code: eng
        Text: English
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      – SubjectFull: Beta lactamases
        Type: general
      – SubjectFull: Density functionals
        Type: general
      – SubjectFull: Gibbs' energy diagram
        Type: general
      – SubjectFull: Electron density
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      – SubjectFull: Beta lactam antibiotics
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      – SubjectFull: Biocatalysis
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      – SubjectFull: Molecular dynamics
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      – TitleFull: Molecular mechanism of nitrocefin hydrolysis by the L1 metallo-β-lactamase: a benchmark study.
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            NameFull: Krivitskaya, Alexandra V.
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            NameFull: Polyakov, Igor V.
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              Text: Feb2026
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              Y: 2026
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