Aging mechanism of soman inhibited acetylcholinesterase.
Aging mechanism of soman inhibited acetylcholinesterase.
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DOI：
10.1021/jp307790v
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发表时间：
2012-09
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影响因子：
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通讯作者：
Gulseher Sarah Sirin;Yanzi Zhou;Lee Lior-Hoffmann;Shenglong Wang;Yingkai Zhang
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作者：
Gulseher Sarah Sirin;Yanzi Zhou;Lee Lior-Hoffmann;Shenglong Wang;Yingkai Zhang
乙酰胆碱酯酶(AChE)是胆碱能神经系统中的一种关键酶，它能分解神经递质乙酰胆碱(ACh)，终止突触信号。乙酰胆碱酯酶的催化丝氨酸可以被最有效的神经毒剂之一梭曼磷酸化，随后发生老化反应。这种磷酸化和衰老过程导致不可逆的AChE抑制，导致突触间隙积累过量的ACh，并导致神经肌肉瘫痪。通过采用Born-Oppenheimer从头算QM/MM伞状取样分子动力学模拟方法，我们表征了梭曼磷酸化AChE的老化机理，并测定了其自由能分布。这种老化反应始于O2-Cα键的断裂，紧随其后的是甲基迁移，并导致第三碳正离子的生成。在过渡态，O2-Cα键已经断裂，平均O-C距离为3.2±0.3；Cα和Cβ碳之间存在甲基迁移，C-C距离分别为1.9±0.1和1.8±0.1；带负电荷的膦酸基通过与催化组氨酸的咪唑环相连的盐桥来稳定。老化的主要产物2，3-二甲基-2-丁醇可以通过水分子的反应迅速形成。我们的特性化机制和模拟结果为这一重要的生化过程提供了新的详细见解。
Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nervous system that hydrolyzes neurotransmitter acetylcholine (ACh) and terminates synaptic signals. The catalytic serine of AChE can be phosphonylated by soman, one of the most potent nerve agents, and subsequently undergo an aging reaction. This phosphonylation and aging process leads to irreversible AChE inhibition, results in accumulation of excess ACh at the synaptic clefts, and causes neuromuscular paralysis. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the aging mechanism of soman phosphonylated AChE and determined its free energy profile. This aging reaction starts with the scission of the O2-Cα bond, which is followed by methyl migration, and results in a tertiary carbenium intermediate. At the transition state, the scissile O2-Cα bond is already cleaved with an average O-C distance of 3.2 ± 0.3 Å and the migrating methyl group is shared between Cα and Cβ carbons with C-C distances of 1.9 ± 0.1 and 1.8 ± 0.1 Å, respectively. The negatively charged phosphonate group is stabilized by a salt bridge with the imidazole ring of the catalytic histidine. A major product of aging, 2,3-dimethyl-2-butanol can be formed swiftly by the reaction of a water molecule. Our characterized mechanism and simulation results provide new detailed insights into this important biochemical process.