Modeling effects of oxyanion hole on the ester hydrolysis catalyzed by human cholinesterases
Modeling effects of oxyanion hole on the ester hydrolysis catalyzed by human cholinesterases
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DOI：
10.1021/jp053736x
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发表时间：
2005-12-08
影响因子：
3.3
通讯作者：
Zhan, CG
中科院分区：
文献类型：
--
作者：
Gao, DQ;Zhan, CG
对乙酰胆碱酯酶（AChE）催化水解乙酰胆碱（ACh）、丁酰胆碱酯酶（BChE）催化水解乙酰胆碱（ACh）、乙酰胆碱酯酶（BChE）催化水解乙酰胆碱（ACh）的反应前酶-底物复合物（ES）、过渡态（TSI）和中间体（INTI）进行了分子动力学（MD）模拟和氢键能（HBE）计算。和BChE催化的（+）/（-）-可卡因的水解，以检查蛋白质环境对催化反应的影响。可卡因与BChE的氧阴离子空穴的氢键作用与乙酰胆碱与AChE/BChE的氢键作用明显不同。AChE/BChE的G121/G116、G122/ G117和A204/A199都能与乙酰胆碱形成氢键，稳定乙酰胆碱水解过程中的过渡态，而BChE仅通过G117和A199与可卡因形成氢键。估计的总HBE从ES到TS 1的变化是大约。-5.4/4.4 kcal/mol的AChE/BChE催化水解ACh和ca. BChE催化的（+）/（-）-可卡因水解为-1.7/-0.8 kcal/mol。AChE/BChE的含氧阴离子空穴对乙酰胆碱水解的能垒的降低作用明显大于BChE对可卡因水解的能垒。这些结果有助于理解为什么乙酰胆碱酯酶对乙酰胆碱的催化活性大大高于BChE对可卡因的催化活性，并为如何提高BChE对可卡因的催化活性提供了有价值的线索。
Molecular dynamics (MD) simulations and hydrogen bonding energy (HBE) calculations have been performed on the prereactive enzyme -substrate complexes (ES), transition states (TSI), and intermediates (INTI) for acetyleholinesterase (AChE)-catalyzed hydrolysis of acetylcholine (ACh), butyry1cholinesterase (BChE)catalyzed hydrolysis of ACh, and BChE-catalyzed hydrolysis of (+)/(-)-cocaine to examine the protein environmental effects on the catalytic reactions. The hydrogen bonding of cocaine with the oxyanion hole of BChE is found to be remarkably different from that of ACh with AChE/BChE. Whereas G121/G116, G122/ G117, and A204/A199 of AChE/BChE all can form hydrogen bonds with ACh to stabilize the transition state during the ACh hydrolysis, BChE only uses G117 and A199 to form hydrogen bonds with cocaine. The change of the estimated total HBE from ES to TS1 is ca. -5.4/4.4 kcal/mol for AChE/BChE-catalyzed hydrolysis of ACh and ca. -1.7/-0.8 kcal/mol for BChE-catalyzed hydrolysis of (+)/(-)-cocaine. The remarkable difference of similar to 3 to 5 kcal/mol reveals that the oxyanion hole of AChE/BChE can lower the energy barrier of the ACh hydrolysis significantly more than that of BChE for the cocaine hydrolysis. These results help to understand why the catalytic activity of AChE against ACh is considerably higher than that of BChE against cocaine and provides valuable clues on how to improve the catalytic activity of BChE against cocaine.