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Spontaneous Reactivation of OPC-Inhibited BChE Mutants: Modeling of Mechanisms

  • CHEMICAL PHYSICS OF BIOLOGICAL PROCESSES
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Abstract

The mechanism of the reactivation reaction of the double mutant butyrylcholinesterase (BChE) double mutantAsn322Glu/Glu325Gly, inhibited by the organophosphorus compound (OPC) echothiophat is studied by molecular modeling methods. The ability of this mutant to spontaneously reactivate itself was previously shown experimentally. The energy profile of the reaction path calculated by the method of quantum mechanics/molecular mechanics (QM/MM) confirms that such a mechanism is possible. Molecular dynamics calculations with QM/MM potentials are used to investigate the proton transfer pathways and determine the protonated state of the glutamic acids in the active site of the double mutant. Possible ways of increasing its conformational stability are investigated by the methods of classical molecular dynamics.

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Funding

This work was financially supported by the Russian Foundation for Basic Research (project no. 19-03-00076), using the equipment of the Interdepartmental Supercomputer Center of the Russian Academy of Sciences and the Center for Shared Use of UltraHigh Performance Computing Resources of Moscow State University.

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Authors and Affiliations

  1. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow, Russia

    S. V. Lushchekina, A. V. Nemukhin, I. V. Polyakov, S. D. Varfolomeev & B. L. Grigorenko

  2. Moscow State University, Moscow, Russia

    A. V. Nemukhin, I. V. Polyakov, S. D. Varfolomeev & B. L. Grigorenko

  3. Institute of Fundamental Medicine and Biology, Kazan Federal (Volga Region) University, Kazan, Russia

    P. Masson

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  1. S. V. Lushchekina
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  2. A. V. Nemukhin
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  3. I. V. Polyakov
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  4. P. Masson
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  5. S. D. Varfolomeev
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  6. B. L. Grigorenko
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Correspondence to A. V. Nemukhin.

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Lushchekina, S.V., Nemukhin, A.V., Polyakov, I.V. et al. Spontaneous Reactivation of OPC-Inhibited BChE Mutants: Modeling of Mechanisms. Russ. J. Phys. Chem. B 16, 103–108 (2022). https://doi.org/10.1134/S1990793122010237

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  • DOI: https://doi.org/10.1134/S1990793122010237

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