Proceedings - Interdisciplinary Center for Nanotoxicity

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46 Conference on Current Trends in Computational Chemistry 2009 Ab Initio Investigation of the Human Acetylcholinesterase (HuAChE)Paraoxon Aging Reaction Pathway Jason Ford‐Green 1, D. Majumdar 1, Jerzy Leszczynski 1 1 Jackson State University, Departement of Chemistry and Biochemistry, Jackson, MS 39217 In the modern age the exposure of humans to harmful organophosphorus (OP) agents has been shown to be exponentialy increasing. Due to the steady rise in deleterious health incidences more must be understood about the physico‐chemical properties mediating such events in comprimised mammalian systems. Towards the elucidation of such events in the human Central Nervous System (CNS), we have carried out ab initio studies to determine the OP‐induced aging pathway regarding O‐O‐diethyl 4‐nitrophenyl phosphate (Paraoxon). Paraoxon acts through the influx of the pesticide into the synaptic cleft or motor endplate and arrests the binding event of acetylcholine to the enzyme Acetylcholinesterase (AChE) (E.C. 3.1.1.7). Previous empirical studies have pointed to the existance of a non‐covalent complex, OP‐Ser203 Adduct, Tetrahedral Intermediate, and the Aged complex as intermediates/states in the evolution this reaction (Aldridge and Reiner, 1972; Main, 1976; Ordentlich, 1996). To this end, we have calculated such states along its reaction pathway. We have carried out thermochemical analyisis at the B3LYP/6‐31++G(d,p) level of theory using the Gaussian03 package. These calculations verified the existenc of a non‐covalent complex, OP‐Ser203 Adduct, Tetrahedral Intermediate, and the Aged complex for one molecule of paraoxon in the gas phase. We have also verified the non‐covalent complex∙∙∙Ser203 Adduct transition state. Where the transition state and low‐energy conformers were verified through IRC, QST2, and harmonic vibrational frequency analysis. Lastly, we will show OP‐Ser203 Adduct∙∙∙Tetrahedral Intermediate and Tetrahedral Intermediate∙∙∙Aged complex transition states with Ea barriers to verify rate determinance and ease of reaction path transition.
Conference on Current Trends in Computational Chemistry 2009 Annular Tautomerism, Electronic Structures, Singlet‐Triplet Gaps, and 1,2‐Rearrangements of Phosphorus Heterocyclic Carbenes (PHCs) Fillmore Freeman* 1, Tiffany Ma 1, Kimberly Marie C. Roth 1, and Stacia A. Sherry 2 1 Department of Chemistry, University of California, Irvine, Irvine, California 92697 2 Santa Rosa Junior College, Santa Rosa, California 95401 and University of California, Davis, Davis, California 95616 Annular tautomerism, aromaticity, electronic structures, isodesmic reactions, partial atomic charges, singlet‐triplet gaps (∆EST), and 1,2‐rearrangements of phosphorus diheterocyclic and triheterocyclic carbenes (PHCs) have been studied using CBS‐QB3, CCSD(T), QCISD(T), B3LYP, PBE1PBE, and MP2. All levels of theory predict significantly larger singlet‐ triplet gaps for the nitrogen heterocyclic carbenes (NHCs) 1,3‐imidazol‐2‐ylidene (1, 83.9 kcal/mol) and 1,2,4‐triazol‐3‐ylidene (2, 85.7 kcal/mol) than for the corresponding PHCs 1,3‐ dihydro‐2H‐1,3‐diphosphol‐2‐ylidene (3, 19.3 kcal/mol) and 1,2,4‐triphosphol‐3‐ylidene (4, 22.5 kcal/mol). The singlet NHCs 1 and 2 have planar structures while the triplet states have envelope conformations with the carbene carbon out of the plane from the other four ring atoms. The PHCs have phosphorus at various levels of pyramidalization and the singlet states of NHCs and PHCs display aromatic character (cyclic 6π electron delocalization). The concerted exothermic 1,2‐rearrangements of the singlet heterocyclic carbenes to their respective five‐ membered heteroaromatics (annular tautomers) proceed through out‐of‐plane cyclic three‐ center transition states. Intrinsic reaction coordinate calculations (IRC) were used to connect the cyclic three‐center transition states to their respective minima. 47
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Proceedings - Interdisciplinary Center for Nanotoxicity

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