8-Oxoguanine （8-oxoG）, a critical mutagenic DNA lesion induced by reactive oxy- gen species, gives rise to a G·C→T·A transversion during replication and thereby must be repaired. The effects of explicit and implicit solvent molecules on the hydrolysis cleavage of N-Glycosidic bond in 8-oxo-7,8-dihydro-2＇-deoxyguanosine （8-oxo-dG） have been systematically clarified in the present work based upon two types of computational models. Detailed potential energy surface （PES） scans and full unconstraint optimizations for all the representative points on PESs were carried out at the B3LYP/6-31＋G（d） level of theory. The effect of implicit solvent was tested by single-point calculation at the SCRF/IEF-PCM model. The results illustrate that the direct hydrolysis model involving one explicit water molecule can’t provide a complete depiction of the hydrolysis process of 8-oxo-dG, attributed to the insufficiency of nucleophile activation and leaving group stabilization. The expansion hydrolysis model involving four explicit water molecules, however, facilitates discrete proton transfer and therefore produces smooth reaction surfaces for both the dissociative （SN1） and concerted （SN2） pathways. The presence of the implicit solvent substantially lowers all activation energies and the SN1 process is more favorable than the SN2 process. The data and insights present here agree well with the experimental results and have given out a baseline for the enzymatic deglycosylation reaction of 8-oxo-dG.
采用BH&HLYP/6-311++g(d,p)方法研究了咖啡因N3和N7位水解代谢机理.每个N位的水解代谢机理考察了两种可能的反应路径:分步的路径A和协同的路径B.计算结果表明:对于N3或N7位水解代谢,路径A均优于路径B;N3位水解代谢的路径A所需的活化自由能(358.8 k J·mol-1)低于N7位(363.1 k J·mol-1),因而代谢产物副黄嘌呤优于茶碱.
