Poly(ADP-ribose) glycohydrolase (PARG) is the only enzyme responsible for the degradation of ADP-ribose polymers. Very recently, the first crystal structure of PARG was reported (Dea Slade, et al., Nature 477 (2011) 616), and a possible SN1-type-like mechanism was proposed. In this work, we present a computational study on the hydrolysis of glycosidic ribose-ribose bond catalyzed by PARG using hybrid density functional theory (DFT) methods. Based on the crystal structure of PARG, three models of the active site were constructed. The calculation results suggest that the degradation of poly(ADP-ribose) follows an SN2 mechanism, and the oxocarbenium expected by Dea Slade is a possible transition state but not an intermediate. The calculated reaction pathway agrees with the proposed mechanism. According to the computational models with different sizes, the roles of key residues are elucidated. Our results may provide useful information for the subsequent experimental and theoretical studies on the structure and functional relationships of PARG.
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