Effects of Explicit and Implicit Solvent Models on the Hydrolysis Cleavage of N-Glycosidic Bond in 8-Oxo-7,8-dihydro-2’-deoxyguanosine

【摘要】 8-Oxoguanine(8-oxoG), a critical mutagenic DNA lesion induced by reactive oxygen 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.更多还原

【Abstract】 8-Oxoguanine(8-oxoG), a critical mutagenic DNA lesion induced by reactive oxygen 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.更多还原