title: Acetylcholinesterase: mechanisms of covalent inhibition of H447I mutant determined by computational analyses.
abstract: The reaction mechanisms of two inhibitor TFK(+) and TFK(0) binding to H447I mutant mouse acetylcholinesterase (mAChE) have been investigated by using a combined ab initio quantum mechanical/molecular mechanical (QM/MM) approach and classical molecular dynamics (MD) simulations. TFK(+) binding to the H447I mutant may proceed with a different reaction mechanism from the wild-type. A water molecule takes over the role of His447 and participates in the bond breaking and forming as a "charge relayer". Unlike in the wild-type mAChE case, Glu334, a conserved residue from the catalytic triad, acts as a catalytic base in the reaction. The calculated energy barrier for this reaction is about 8kcal/mol. These predictions await experimental verification. In the case of the neutral ligand TFK(0), however, multiple MD simulations on the TFK(0)/H447I complex reveal that none of the water molecules can be retained in the active site as a "catalytic" water. Taken together our computational studies confirm that TFK(0) is almost inactive in the H447I mutant, and also provide detailed mechanistic insights into the experimental observations.
authors.affiliation: Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0365, USA. ycheng@mccammon.ucsd.edu
authors.forename: Y H
authors.initials: YH
authors.lastname: Cheng
authors.forename: X L
authors.initials: XL
authors.lastname: Cheng
authors.forename: Z
authors.initials: Z
authors.lastname: Radić
authors.forename: J A
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects* / Q000235:genetics; D000818:Animals; D002384:Catalysis; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D011789:Quantum Theory
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase