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 C[H.sub.2]N[O.sup.-] 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, C[H.sub.2]N[O.sup.-]-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. Key words: tabun, aging mechanism, reactivation mechanism, QM/MM method. Le tabun, un compose organophosphore, est extremement neurotoxique en raison de son inhibition irreversible de l'acetylcholinesterase (AChE). Il a ete utilise comme arme chimique. Dans ce travail, faisant appel a la methode de mecanique quantique / mecanique moleculaire (MQ/MM), on a etudie le vieillissement et le mecanisme de reactivation de de l'AChE inhibee par le tabun. On a effectue l'optimisation de la geometrie des points stationnaires au niveau B3LYP/6- 31G(d) de la theorie. On a calcule les energies des points uniques au niveau B3LYP/6-3111++G(d,p) de la theorie. Sur la base des resultats de methode de MQ/MM, il est possible d'arriver a une conclusion a l'effet que, dans le mecanisme de vieillissement, la scission de la liaison C-O est causee par l'attaque d'une molecule d'eau sur le groupe ethoxy. Le processus de reactivation initie par les antidotes C[H.sub.2]N[O.sup.-] ou HLO-7 comporte trois etapes elementaires, l'attaque nucleophile sur l'atome de phosphore par l'antidote, le processus de dephosphorylation et la decomposition du complexe antidote-tabun. La barriere d' energie la plus elevee de la reaction de vieillissement, la reactivation induite par le C[H.sub.2]N[O.sup.-] et la reactivation induite par le HLO-7 sont respectivement de 19,9, 20,0 et 14,8 kcal/mol (1 cal = 4.184 J). Le niveau relativement plus bas de l'energie d' activation globale pour la reactivation induite par le HLO-7 comparee a celle de la reaction de vieillissement indique que le HLO-7 peut reactiver l'AChE inhibee par le tabun. De plus, la possibilite qu'un nouvel antidote puisse reactiver l'AChE inhibee par le tabun a ete examinee par l'inequation X < 19,9 kcal/mol dans laquelle X correspond a la barriere d'energie la plus elevee de la reaction de reactivation du nouvel antidote mis au point. Mots-cles : tabun, mecanisme de vieillissement, mecanisme de reactivation, methode MQ/MM. [Traduit par la Redaction]
Introduction Organophosphorus (OP) compounds, such as paraoxon, methamidophos, VX, and tabun, have been used as insecticides in modern agriculture or as chemical warfare agents in the military. The broad distribution [...]