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Intermolecular interactions of the extended recognition site of VIM-2 metallo-β-lactamase with 1,2,4-triazole-3-thione inhibitors. Validations of a polarizable molecular mechanics potential by ab initio QC.

Authors
  • Kwapien, Karolina1, 2, 3
  • Gavara, Laurent4
  • Docquier, Jean-Denis5
  • Berthomieu, Dorothée3
  • Hernandez, Jean-François4
  • Gresh, Nohad2
  • 1 Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université de Paris UMR 8601, Paris, France. , (France)
  • 2 Laboratoire de Chimie Théorique, Paris, France. , (France)
  • 3 Institut Charles Gerhardt, UMR 5253, CNRS, Université de Montpellier, ENSCM, Montpellier, France. , (France)
  • 4 Institut des Biomolécules Max Mousseron, UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, Montpellier, France. , (France)
  • 5 Dipartimento di Biotecnologie Mediche, Università di Siena, Siena, Italy. , (Italy)
Type
Published Article
Journal
Journal of Computational Chemistry
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 15, 2021
Volume
42
Issue
2
Pages
86–106
Identifiers
DOI: 10.1002/jcc.26437
PMID: 33169865
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Molecular dynamics on the complexes of inhibitors with Zn-metalloproteins are a privileged area of applications of polarizable molecular mechanics potentials. With which accuracy could these reproduce the QC intermolecular interaction energies in the two mono-zinc cores and in the dizinc core, toward full-fledged MD simulations on the entire protein complexes? We considered the complexes of the extended recognition site of a Zn-dependent metallo-β-lactamase, VIM-2, produced by bacteria responsible for nosocomial infections, with five newly synthesized inhibitors sharing an original dizinc binding group, 1,2,4-triazole-3-thione (TZT). We considered the energy-minimized structures of each of the five VIM-2 complexes obtained with the SIBFA potential. Energy decomposition analyses (EDA) at the HF level enabled to compare the QC and the SIBFA ΔE values and their contributions in the zinc cores, with and without TZT, totaling 30 complexes. With one exception, the ΔE(QC) values were reproduced with relative errors <1.5%. We next considered the complex of the entire inhibitors with an extended model of VIM-2 recognition site, totaling up to 280 atoms. ΔE(SIBFA) could closely reproduce ΔE(QC). EDA analyses were resumed on the complexes of each inhibitor arm with its interacting VIM-2 residues. As a last step, EDA results at correlated levels were analyzed for the mono- and dizinc sites enabling comparisons with dispersion-augmented ΔE(SIBFA) and correlated multipoles and polarizabilities. Closely reproducing ΔE(QC) and the contrasting trends of its individual contributions should enable for dependable free energy perturbation studies and comparisons to recent experimental ΔG values, limiting as much as possible the reliance on error compensations. © 2020 Wiley Periodicals LLC.

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