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

peer reviewedAbstract 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

Calibration of 1,2,4-Triazole-3-Thione, an Original Zn-Binding Group of Metallo-β-Lactamase Inhibitors. Validation of a Polarizable MM/MD Potential by Quantum Chemistry

In the context of the SIBFA polarizable molecular mechanics/dynamics (PMM/PMD) procedure, we report the calibration and a series of validation tests for the 1,2,4-triazole-3-thione (TZT) heterocycle. TZT acts as the chelating group of inhibitors of dizinc metallo-β-lactamases (MBL), an emerging class of Zn-dependent bacterial enzymes, which by cleaving the β-lactam bond of most β-lactam antibiotics are responsible for the acquired resistance of bacteria to these drugs. Such a study is indispensable prior to performing PMD simulations of complexes of TZT-based inhibitors with MBL’s, on account of the anchoring role of TZT in the dizinc MBL recognition site. Calibration was done by comparisons to energy decomposition analyses (EDA) of high-level <i>ab initio</i> QC computations of the TZT complexes with two probes: Zn­(II), representative of “soft” dications, and water, representative of dipolar molecules. We performed distance variations of the approach of each probe to each of the two TZT atoms involved in Zn ligation, the S atom and the N atom <i>ortho</i> to it, so that each SIBFA contribution matches its QC counterpart. Validations were obtained by performing in- and out-of-plane angular variations of Zn­(II) binding in monoligated Zn­(II)–TZT complexes. The most demanding part of this study was then addressed. How well does Δ<i>E</i>(SIBFA) and its individual contributions compare to their QC counterparts in the dizinc binding site of one MBL, L1, whose structure is known from high-resolution X-ray crystallography? Six distinct complexes were considered, namely each separate monozinc site, and the dizinc site, whether ligated or unligated by TZT. Despite the large magnitude of the interaction energies, in all six complexes Δ<i>E</i>(SIBFA) can match Δ<i>E</i>(QC) with relative errors <2% and the proper balance of individual energy contributions. The computations were extended to the dizinc site of another MBL, VIM-2, and its complexes with two other TZT analogues. Δ<i>E</i>(SIBFA) faithfully reproduced Δ<i>E</i>(QC) in terms of magnitude, ranking of the three ligands, and trends of the separate energy contributions. A preliminary extension to correlated calculations is finally presented. All these validations should enable a secure design of a diversity of TZT-containing MBL inhibitors: a structurally and energetically correct anchoring of TZT should enable all other inhibitor groups to in turn optimize their interactions with the other target MBL residues