Phosphonylation and aging mechanisms of mipafox and butyrylcholinesterase: A theoretical study |
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Authors: | Jun Ding Yuan Yao Hui Zhang ZeSheng Li |
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Institution: | 1. College of Material Science and Engineering, Harbin University of Science and Technology, Harbin, 150080, China 2. Academy of Fundamental and Interdisciplinary Sciences, Harbin Institute of Technology, Harbin, 150000, China 3. Key Laboratory of Cluster Science of Ministry of Education & School of Chemistry, Beijing Institute of Technology, Beijing, 100081, China
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Abstract: | Phosphonylation and aging processes between butyrylcholinesterase with mipafox have been studied at the B3LYP/6-311G(d,p) level of theory. The calculated results indicate that the phosphonylation process employs a two-step addition-elimination mechanism with the addition (the first step) as the rate-limiting step. Two different calculation models revealed that the catalytic triad of butyrylcholinesterase plays an important role in accelerating the reaction. This is the same mechanism as the phosphonylation reaction of acetylcholinesterase by sarin reported by Wang et al. However, the energy barrier of the rate-limiting step in the present reaction is higher than that in phosphonylation reaction of acetylcholinesterase by sarin. This indicates the differences in the phosphonylation activity of sarin and mipafox. The aging process occurs through a two-step addition-elimination mechanism similar to the phosphonylation process with the addition as the rate-limiting step. The solvent effects have been evaluated by using a CPCM model and the results show that the stationary structures and the negative charges around some important atoms involved in the two processes are not significantly different. However, the energy barrier of the phosphonylation process is remarkably decreased, revealing that this process is feasible in solution. |
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