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Molecular Modeling Evidence for His438 Flip in the Mechanism of Butyrylcholinesterase Hysteretic Behavior

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Abstract

Cholinesterases display a hysteretic behavior with certain substrates and irreversible inhibitors. For years, this behavior has remained puzzling. However, several lines of evidence indicated that it is caused by perturbation of the catalytic triad and its water environment. In the present study, using molecular dynamics simulations of Ala328Cys BuChE mutant and wild-type BuChE in the absence and presence of a co-solvent (sucrose, glycerol), we provide evidence that hysteresis originates in a flip of the catalytic triad histidine (His438). This event is controlled by water molecules that interact with active site residues. The physiological significance of this phenomenon is still an issue.

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Acknowledgments

This work was partly supported by the Russian Foundation for Basic Research (project 12-03-31039-mol_a) and Fellowship of the President of Russia (СП-185.2012.4). We thank the Supercomputing Center of Lomonosov Moscow State University for providing computational facilities. We thank Prof. Vytas Švedas (Lomonosov Moscow State University) for valuable discussion.

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Authors and Affiliations

  1. Computer Modeling of Biomolecular Systems Lab, N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosygina St., 119334, Moscow, Russia

    Sofya V. Lushchekina, Alexander V. Nemukhin & Sergei D. Varfolomeev

  2. Chemistry Department, M.V. Lomonosov Moscow State University, Moscow, Russia

    Alexander V. Nemukhin & Sergei D. Varfolomeev

  3. Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198-5950, USA

    Patrick Masson

  4. DYNAMOP, Institut de Biologie Structurale, 6 rue Jules Horowitz, 38000, Grenoble, France

    Patrick Masson

Authors
  1. Sofya V. Lushchekina
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  2. Alexander V. Nemukhin
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  3. Sergei D. Varfolomeev
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  4. Patrick Masson
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Correspondence to Sofya V. Lushchekina.

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Lushchekina, S.V., Nemukhin, A.V., Varfolomeev, S.D. et al. Molecular Modeling Evidence for His438 Flip in the Mechanism of Butyrylcholinesterase Hysteretic Behavior. J Mol Neurosci 52, 434–445 (2014). https://doi.org/10.1007/s12031-013-0178-2

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  • DOI: https://doi.org/10.1007/s12031-013-0178-2

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