Modeling reactivation of the phosphorylated human butyrylcholinesterase by QM(DFTB)/MM calculations

Author:

Kulakova Anna1,Lushchekina Sofya2,Grigorenko Bella12,Nemukhin Alexander12

Affiliation:

1. Chemistry Department, M. V. Lomonosov Moscow State University, 1-3 Leninskiye Gory, Moscow 119991, Russia

2. N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 Kosygin Street, Moscow 119334, Russia

Abstract

Human butyrylcholinesterase (BChE) is a bioscavenger that protects the enzyme which is critical for the central nerve system, acetylcholinesterase, from poisoning by organophosphorus agents. Elucidating the details of the hydrolysis reaction mechanism is important to understand how the phosphorylated BChE can be reactivated. Application of the QM(DFTB)/MM(AMBER) method to construct the minimum energy pathways for the hydrolysis reaction of the diethylphosphorylated BChE allowed us to suggest a mechanism of reactivation of the wild-type and the G117H mutated enzyme. Unlike previous approaches assuming that either His438 or His117 serves as a general base in the catalysis, in our proposal the Glu197 residue is responsible for activation of the nucleophilic water molecule (Wat) leading to the chemical transformations that restore the catalytic Ser198 residue in BChE. In agreement with the experimental data, it is shown that the G117H mutation facilitates the reactivation of the inhibited enzyme.

Publisher

World Scientific Pub Co Pte Lt

Subject

Computational Theory and Mathematics,Physical and Theoretical Chemistry,Computer Science Applications

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