| Organophosphate (OP) compounds have been widely used over decades for protecting crops, livestock and human health (household pest controlling). The usage of OPs can affect inversely for non-targeted species such as insects, fish, birds and mammals including humans. The primary target of OPs in organisms is acetylcholinesterase (AChE), which is an important enzyme located in the central and peripheral nervous system of organisms. The natural acetylcholine (ACh) regulatory mechanism by AChE can be disrupted by an array of compounds that have different chemical and structural characteristics. We mainly focus on inhibition of AChE by OP compounds.;In the first part of the study, we computationally studied selected OPs to determine their structure and up to 12 different mechanisms of reaction with methanol. Methanol is chosen as a surrogate molecule to represent the serine residue and imidazole to represent histidine in the active site of AChE, the target enzyme. Transition states and intermediates along several plausible reaction pathways are computed, along with activation enthalpies, entropies, and free energies. Pathways for different leaving groups are also analyzed. Water effect for the reactions also accounted using a polarized continuum model of implicit solvation. Composite rate constants were calculated using a steady-state analysis for mechanisms with more than one activation barrier. Mechanisms explored fall into two main categories, direct and indirect, all involving proton transfer from the methanol hydroxyl group to the leaving group. The indirect proton-transfer mechanism relays the proton through the phosphinyl oxygen, and the leaving group is positioned on the opposite side to the incoming hydroxyl nucleophile in a distorted trigonal bipyramidal transition state. We explored mechanisms in which one or two water molecules and/or an imidazole molecule assisted in the proton transfer. Generally speaking, whether direct or indirect, the lowest activation energies were obtained for mechanisms in which the phosphinyl oxygen plays a role in transfer, and additionally water assistance (ubiquitous in the enzyme active site) lowers activation barriers.;In the second part of this study, we have performed protein and ligand docking, and molecular dynamic calculations to validate the reaction mechanisms found in the first part of study and to find important parameters and behavioral activities of OPs on their targeted biological system AChE. We have considered ten OP compounds with AChE in this portion of study. Our results show that, depending on the size of the OPs, they tend to interact within two distinct locations in the active site of AChE. Acute OP poisoning hypothetically could be happening in the reaction site that (at Ser199) is in the deepest part of the active site by relatively smaller OP compounds, while acute poisoning can be predicted by relatively larger OP compounds in the secondary reaction site (at Tyr327). Water mediated proton transfer can be the most potent reaction initiation mechanism between OPs and AChE in both Ser199 and Tyr327 sites. Based on the evidence we propose potential reaction mechanisms between OPs and AChE in the secondary reaction site. |
