Characterization of a complete cycle of acetylcholinesterase catalysis by <Emphasis Type="Italic">ab initio</Emphasis> QM/MM modeling |
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Authors: | Alexander V Nemukhin Sofia V Lushchekina Anastasia V Bochenkova Anna A Golubeva Sergei D Varfolomeev |
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Institution: | (1) N.M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, 4 ul. Kosygina, Moscow, 119334, Russian Federation;(2) Department of Chemistry, M.V. Lomonosov Moscow State University, 1/3 Leninskie Gory, Moscow, 119991, Russian Federation |
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Abstract: | The reaction mechanism of acetylcholine hydrolysis by acetylcholinesterase, including both acylation and deacylation stages
from the enzyme-substrate (ES) to the enzyme-product (EP) molecular complexes, is examined by using an ab initio type quantum mechanical – molecular mechanical (QM/MM) approach. The density functional theory PBE0/aug-6–31+G* method for
a fairly large quantum part trapped inside the native protein environment, and the AMBER force field parameters in the molecular
mechanical part are employed in computations. All reaction steps, including the formation of the first tetrahedral intermediate
(TI1), the acylenzyme (EA) complex, the second tetrahedral intermediate (TI2), and the EP complex, are modeled at the same
theoretical level. In agreement with the experimental rate constants, the estimated activation energy barrier of the deacylation
stage is slightly higher than that for the acylation phase. The critical role of the non-triad Glu202 amino acid residue in
orienting lytic water molecule and in stabilizing the second tetrahedral intermediate at the deacylation stage of the enzymatic
process is demonstrated.
Figure The computed energy diagram for the reaction path from the enzyme – substrate complex (ES) to the enzyme-product complex (EP). |
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Keywords: | Acetylcholinesterase Acetylcholine hydrolysis QM/MM modeling Reaction mechanism |
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