Interaction of antibiotics with the active site of metal-beta-lactamase: reconstruction of electronic factors

Krivitskaya A.V., Khrenova M.G.1, Tsirelson V.G.

Mendeleev University of Chemical Technology, Moscow, Miusskaya Sq. 9

1Lomonosov Moscow State University, Chemistry Department, Leninskie Gory, 1

The emerging problem nowadays is the increase of resistance of bacteria to many of the existing antibiotics. One of the reasons is hydrolysis of antibiotics by metallo-beta-lactamases; thus understanding the details of the reaction mechanism in the active site is required for further analysis of the reasons of hydrolysis of certain antibiotics and resistance of others. We present a new interdisciplinary study combining methods applied for modeling large biological systems and modern approaches of precise analysis of the electronic structure and reactivity of small molecules. According to the literature data, a relatively stable intermediate is formed during this reaction, and its further decomposition to reaction products is a limiting step. At the first step, the QM/MM method at the DFT(PBE0-D3/6-31**)/AMBER level of theory is used to construct the equilibrium geometry configurations of protein complexes with stable intermediates of hydrolysis of various antibiotics. Next, for a large molecular cluster containing the substrate, zinc cations and amino acid residues of the active site, key geometric parameters, as well as electron density and electrostatic potential on the van der Waals surface surrounding the cluster were analyzed. This allowed us to reveal the details of substrate interactions with the reaction participants in the active site. In addition, the distribution of the total potential acting on the electron in the active site is calculated. This potential includes both electrostatic and exchange (quantum) components, providing a more complete characterization of interactions realized during the reaction. Thus, as a result of this work, physically justified simple and effective molecular descriptors determining the resistance of antibiotics to metal-beta-lactamases have been proposed and applied.

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