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The role of active-site residues in the dealkylation reaction in the P(S)C(S) diastereomer of 2-(3,3-dimethylbutyl)methylphosphonofluoridate (soman)-inhibited Torpedo californica acetylcholinesterase (AChE) was investigated by full-scale molecular dynamics simulations using CHARMM: &gt;400 ps equilibration was followed by 150-200 ps production runs with the fully solvated tetracoordinate phosphonate adduct of the wild-type, Trp84Ala and Gly199Gln mutants of AChE. Parallel simulations were carried out with the tetrahedral intermediate formed between serine-200 Ogamma of AChE and acetylcholine. We found that the NepsilonH in histidine H(+)-440 is positioned to protonate the oxygen in choline and thus promote its departure. In contrast, NepsilonH in histidine H(+)-440 is not aligned for a favourable proton transfer to the pinacolyl O to promote dealkylation, but electrostatic stabilization by histidine H(+)-440 of the developing anion on the phosphonate monoester occurs. Destabilizing interactions between residues and the alkyl fragment of the inhibitor enforce methyl migration from Cbeta to Calpha concerted with C-O bond breaking in soman-inhibited AChE. Tryptophan-84, phenyalanine-331 and glutamic acid-199 are within 3.7-3.9 A (1 A=10(-10) m) from a methyl group in Cbeta, 4.5-5.1 A from Cbeta and 4.8-5.8 A from Calpha, and can better stabilize the developing carbenium ion on Cbeta than on Calpha. The Trp84Ala mutation eliminates interactions between the incipient carbenium ion and the indole ring, but also reduces its interactions with phenylalanine-331 and aspartic acid-72. Tyrosine-130 promotes dealkylation by interacting with the indole ring of tryptophan-84. Glutamic acid-443 can influence the orientation of active-site residues through tyrosine-421, tyrosine-442 and histidine-440 in soman-inhibited AChE, and thus facilitate dealkylation.

Molecular dynamics study of active-site interactions with tetracoordinate transients in acetylcholinesterase and its mutants