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

Transformation pathways of MeO-PBDEs catalyzed by active center of P450 enzymes: A DFT investigation employing 6-MeO-BDE-47 as a case

“…The current study, together with our previous studies , indicates that with the fast advancement of human computational capacity, it becomes feasible to employ the DFT calculation to predict the biotransformation pathways and products of xenobiotics catalyzed by the active species of CYPs. With the computation-intensive hybridization method of quantum mechanics/molecular mechanics (QM/MM) Bren and Oostenbrink, 2012;Li et al, 2012Li et al, , 2014Tang et al, 2014), the protein environment can also be simulated, which is a future direction of the research. Thus, the method can be potentially employed to develop computational toxicology models, e.g.…”

QM/MM study on the aging mechanism of dichlorvos-inhibited acetylcholinesterase

“…The second stage is either a reactivation process by dephosphorylation in which the hydroxyl oxygen of Ser203 leaves the P atom or an aging process by dealkylation in which another ester group of the OP compound leaves the P atom resulting in an "aged" enzyme which cannot be reactivated [12]. Previous studies [13][14] revealed that most OP-inhibited-AChE adducts (dichlorvos, sarin, paraoxon, tabun, VX, etc.) execute the dealkylation reaction through the C-O bond scission process in which the alphacarbon atom of alkoxyl in OP compound is attacked by a nucleophilic water molecule.…”

“…The mechanism is provided in Figure S1 of Supplementary data. In the aging process, it is Glu202 residue that acts as proton acceptor rather than His447 which is protonated through the phosphorylation reaction [13]. In other words, His447 is not directly involved in the dealkylation reaction.…”

“…Although various experimental techniques including X-ray crystallography have been used, the aging mechanism of OP-inhibited-AChE still remains elusive [13][14].…”

“…The internuclear distances, O β -N ε and N ε -P, keep almost unchanged during the process from the reactant to the transition state, but change dramatically in the process from the transition state to the product. As presented in Figure 2, the H ε atom of A c c e p t e d M a n u s c r i p t 13 In order to further ascertain the influence of the H ε atom in His447 on the aging reaction, the charge analysis is carried out for the unprotonated and protonated systems. The atomic charges of the crucial atoms, O β , O ω and N ε , along the reaction coordinate are depicted in Figure 3.…”