Theoretical study on the aging and reactivation mechanism of tabun-inhibited acetylcholinesterase by using the quantum mechanical/molecular mechanical method

The organophosphorous compound tabun is highly neurotoxic because of its irreversible inhibition on acetylcholinesterase (AChE). It is wildly used as a warfare agent in the military. In this work, the aging and reactivation mechanism of tabun-inhibited AChE were studied by using the quantum mechanical/molecular mechanical (QM/MM) method. Geometry optimization of the stationary points were performed at the B3LYP/6-31G(d) level. Single-point energies were computed at the B3LYP/6-311++G(d, p) level. On the basis of the QM/MM results, a conclusion that the C-O bond scission is caused by water attack on the ethoxy group in the aging mechanism can be drawn. The reactivation process initialed by the antidotes CH2NO- or HLO-7 consists of three elemental steps, the nucleophilic attack on the P atom by the antidote, the dephosphorylation process, and the decomposition of the antidote-tabun complex. The highest energy barriers of the aging reaction, CH2NO--induced reactivation, and HLO-7-induced reactivation are 19.9, 20.0, and 14.8 kcal/mol (1 cal = 4.184 J), respectively. The relative lower overall energy barrier of HLO-7-induced reactivation compared with that of the aging reaction indicates that HLO-7 is able to reactivate tabun-inhibited AChE. In addition, whether a newly designed antidote is able to reactivate tabun-inhibited AChE can be examined by the inequation X < 19.9 kcal/mol, where X means the highest energy barrier of the reactivation reaction of the newly designed antidote.