Molecular mechanics and dynamics combined with semiempirical calculations were carried out for purposes of comparison of the active site characteristics of AChE,1 trypsin, and chymotrypsin as probed by their diastereomeric adducts with 2-(3,3-dimethylbutyl) methylphosphonofluoridate (soman), methylphosphonate monoester anions, and tetravalent carbonyl intermediates of the reactions of the natural substrates in each case. Glul99 is a key residue in the electrostatic catalytic mechanism of AChE, in removal of the leaving group, and possibly by acting as an alternate general base catalyst. “Pushing” of an alkoxy ligand by Glul99 and the numerous small van der Waals interactions promote dealkylation in phosphonate adducts of AChE much more effectively than any other enzyme. A high concentration of negative charge created by the phosphonate ester monoanion and Glul99 adjacent to it fully accounts for the resistance to the attack of even the strongest nucleophile applied for enzyme reactivation. Stabilization of the developing negative charge on the phosphonates in the soman-inhibited PsCs adducts of serine hydrolases is by electrophilic residues in the oxyanion hole (AChE) and the protonated catalytic His. PR diastereomers of soman-inhibited AChE can be accommodated in an orientation in which the oxyanion hole interactions are lost and for which the stabilizing interactions are 17-26 kcal/mol smaller than in the Ps diastereomer.2 The dealkylation reaction is almost equally likely in all diastereomers of somaninhibited AChE. The stabilizing interaction energies are ~4 kcal/mol greater in the PR than in the Ps adducts of the soman-inhibited serine proteases. There is 0.60 unit greater partial negative charge on the phosphonyl fragment in the anion of phosphonate monoesters of Ser than at the oxygens of tetravalent carbonyl transients resulting in ~12-22 kcal/mol greater stabilization of the former than the latter.
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