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Molecular Modeling Evidence for His438 Flip in the Mechanism of Butyrylcholinesterase Hysteretic Behavior |
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| Authors: | Sofya V. Lushchekina Alexander V. Nemukhin Sergei D. Varfolomeev Patrick Masson |
| Affiliation: | 1. Computer Modeling of Biomolecular Systems Lab, N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosygina St., 119334, Moscow, Russia 2. Chemistry Department, M.V. Lomonosov Moscow State University, Moscow, Russia 3. Eppley Institute, University of Nebraska Medical Center, Omaha, NE, 68198-5950, USA 4. DYNAMOP, Institut de Biologie Structurale, 6 rue Jules Horowitz, 38000, Grenoble, France |
| 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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