Reaction pathway for reactivation and aging of paraoxon-inhibited-acetylcholinesterase: A QM/MM study

The organophosphorus pesticide paraoxon is an acetylcholinesterase (AChE) inhibitor which can destroy the function of acetylcholinesterase. In this work, the reactivation and aging mechanism of paraoxon-inhibited AChE complex were studied by using the QM/MM method. Geometries of the stationary points were optimized at the B3LYP/6-31G(d)//CHARMM22 level and the single-point energies were calculated at the B3LYP/6-311++G(d,p)//CHARMM22 level. Studies show that the reactivation process of paraoxon–AChE complex involves the formation, reorganization and dissociation of the trigonal bipyramidal shaped pentacoordinated phosphorus compound, and the formation of this phosphorus compound is the rate determining step with an energy barrier of 29.0 kcal/mol. The aging process of paraoxon–AChE complex proceeds via a carbocation shaped transition state with an energy barrier of 26.8 kcal/mol. Moreover, the nucleophilic water molecule between residue His447 and Glu202 is more feasible to participate in the reactivation process than aging process, whereas the aging process is promoted by the water molecule on the other side of residue Glu202. Furthermore, Gly122 is the major promoter for both dephosphorylation and dealkylation process, while Gly121 and Tyr133 are the main obstacles for dephosphorylation and dealkylation process, respectively.