title: On quantum mechanical--molecular mechanical (QM/MM) approaches to model hydrolysis of acetylcholine by acetylcholinesterase.
abstract: We re-visited the results of quantum mechanics--molecular mechanics (QM/MM) approaches aiming to construct the reaction energy profile for the acylation stage of acetylcholine hydrolysis by acetylcholinesterase. The main emphasis of this study was on the energy of the first tetrahedral intermediate (TI) relative to the level of the enzyme-substrate (ES) complex for which contradictory data from different works had been reported. A new series of stationary points on the potential energy surface was calculated by using electronically embedding QM/MM schemes when starting from the crystal structure mimicking features of the reaction intermediate (PDB ID: 2VJA). A thoughtful analysis allows us to conclude that the energy of TI should be lower than that of ES, and a proper treatment of contributions from the oxyanion hole residues accounts for their relative positions.
authors.affiliation: Department of Chemistry, M.V. Lomonosov Moscow State University, 1/3 Leninskie Gory, Moscow 119991, Russian Federation. anemukhin@yahoo.com
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Nemukhin
authors.forename: Bella L
authors.initials: BL
authors.lastname: Grigorenko
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Morozov
authors.forename: Mikhail S
authors.initials: MS
authors.lastname: Kochetov
authors.forename: Sofya V
authors.initials: SV
authors.lastname: Lushchekina
authors.forename: Sergei D
authors.initials: SD
authors.lastname: Varfolomeev
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000737:chemistry* / Q000378:metabolism*; D000215:Acylation; D000818:Animals; D018360:Crystallography, X-Ray; D006868:Hydrolysis; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D011789:Quantum Theory; D013379:Substrate Specificity; D014101:Torpedo
chemical_list: D000110:Acetylcholinesterase; D000109:Acetylcholine