This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Organophosphates (OP) make up by far the largest class of insecticides in use today. Controlling OP insecticide toxicity to humans, while at the same time maintaining their effectiveness against insect pests, is an important public health and economic goal. It is well known that the primary acute toxicity of OP agents arises from the phosphorylation of the active site Serine in the enzyme acetylcholinesterase (AChE) by the oxon metabolite of the OP. The objective of this project is to use molecular dynamics simulations to determine the mechanism of effect of OP insecticide metabolites on AChE. Our central hypothesis, based on our preliminary data, is that the reaction of OP insecticide oxon metabolites with AChE proceed through a several-step mechanism involving an initial complex where the oxon sits in the entrance channel and where the binding energy of this complex determines the toxicity of the oxon, a second complex where the protein has rearranged to allow the oxon into the AChE binding site, and finally the phosphorylation reaction. The rationale for the proposed research is that once we have a clear mechanistic understanding of how the oxons and AChE react, it is expected that it will become possible to control these reactions through design of new OP agents. This will lead to the possibility of developing more effective and safer OP agents, as well as developing temporary AChE inhibitors.
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