School of Pharmaceutical Sciences, East Campus, Sun Yat-sen University, Guangzhou 510006, China.
J Phys Chem B. 2012 Feb 16;116(6):1984-91. doi: 10.1021/jp211403j. Epub 2012 Feb 2.
Although various T. vivax purine-specific inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH) crystal structures were determined in recent years, the mechanistic details for the cleavage of N-glycosidic bond and the release of base are still unclear. Herein, the irreversible hydrolysis reaction has been studied by ab initio QM/MM MD simulations, and the results indicate a highly dissociative and concerted mechanism. The protonation of substrate at N7 of inosine is found to strongly facilitate the hydrolysis process, while the hydrolysis reaction is less sensitive to the protonation state of Asp 40 residue. The proton-transfer channel and the dependence of activity on the anti/syn-conformation of substrate are also explored.
尽管近年来已经确定了各种间日疟原虫嘌呤特异性肌苷-腺嘌呤-鸟嘌呤核苷核苷水解酶（IAG-NH）晶体结构，但 N-糖苷键断裂和碱基释放的机制细节仍不清楚。在此，通过从头算 QM/MM MD 模拟研究了不可逆水解反应，结果表明该反应具有高度离解和协同的机制。在肌苷的 N7 位质子化被发现可强烈促进水解过程，而水解反应对 Asp 40 残基的质子化状态的敏感性较低。还探索了质子转移通道以及活性对底物顺/反构象的依赖性。
