Acetylcholinesterase (AChE) is an enzyme that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into acetic acid and choline. The enzyme regulates the levels of acetylcholine in the brain, ensuring effective signaling between neurons and optimal neurological function. Inhibitory compounds that bind to AChE and inactivate the enzyme can thus cause side effects that include paralysis, seizures, asphyxiation, and finally death. Such compounds are known as organophosphates (OPs), like sarin or tabun which are used (but prohibited) as war nerve agents. Other OPs are still being used in herbicides and pesticides today despite the risk of poisoning. Chronic exposure to OPs poses a major threat to public health. Oximes and their ability to restore activity of inhibited AChE are thus a significant area of research. Oximes are compounds that can reactivate an OP inhibited AChE by breaking the bond between the organophosphate and the key serine residue of the active site. The aim of this project was to scrutinize the reaction of the oxime after the reactivation of an OP-inhibited AChE to determine the mechanism of the oxime degradation. We hoped to achieve a better understanding of the active site environment of AChE on the behavior of the oxime. To do this, the project utilized quantum mechanical (QM) and molecular mechanical (MM) simulations, a series of hybrid computations used to calculate the energies of atoms and molecules, to study the active site environment and investigate the mechanism of oxime degradation. Specifically, we chose to study a non-pyridinium oxime, TAB2OH. Our investigation was guided by key questions we hoped to answer, including: does oxime degradation occur inside or outside of the active site of AChE? Additionally, we planned to elucidate the differences in properties between pyridinium and non-pyridinium oximes. Ultimately, discoveries in this field may be applied to the design of therapeutic compounds against OP poisoning.

Understanding the fate of products after reactivation of acetylcholinesterase with QM/MM simulations

2019 Spring National Meeting

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