QM/MM study on the spontaneous reactivation mechanism of (±)methamidophos-inhibited-acetylcholinesterase

Abstract As an organophosphorus pesticide with high toxicity, methamidophos has been used globally to control a variety of pest insects. It can inhibit acetylcholinesterase (AChE) of nerve cell and cause respiratory failure or even death. In this work, the spontaneous reactivation mechanism of (−)-MeP-inhibited human AChE (Path A) and (+)-MeP-inhibited human AChE (Path B or path C) was studied with QM/MM method. All the intermediates and transition states were optimized at the B3LYP/6-31G(d)//CHARMM22 level, and single point energies of these optimized geometries were calculated at the B3LYP/6-311++G(d,p)//CHARMM22 level. This study reveals that the spontaneous reactivation mechanism is composed of three steps, i.e. , the nucleophilic attack on the P atom by a water molecule, the reorganization step, and the dephosphorylation step. The nucleophilic attack is the rate-determining step. All the intermediates of the three paths exhibit the trigonal bipyramidal character. The highest energy barriers of path A, path B and path C are 22.7 kcal/mol, 20.0 kcal/mol and 25.6 kcal/mol, respectively. This indicates that path B initiated by H 2 O ω is the dominate spontaneous reactivation pathway of (+)-MeP-inhibited human AChE. Compared with path A, the relatively lower energy barrier of path B indicates that (+)-MeP-inhibited human AChE is more feasible to be spontaneously reactivated than (−)-MeP-inhibited human AChE.