QM/MM molecular dynamics study of purine-specific nucleoside hydrolase.

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.