Theoretical Insight Into 7,8-Dihydrogen-8-Oxoguanine Radical Cation Deprotonation

7,8-Dihydro-8-oxoguanine (8-oxoG) has attracted considerable attention from analysts because it is collected with GC -> TA transversions in DNA replication; especially, due to the lower redox potential compared to guanine, 8-oxoG is considered to be the ultimate "positive hole" sink, where the oxidation of DNA is funneled into this direction. Thus, lots of efforts have been made on the one-electron oxidation of 8-oxoG and the ensuing deprotonation reaction. However, there still have been some inconsistent results and the deprotonation mechanism of 8-oxoG(+) remains elusive to a larger extent in previous studies. Herein, we performed a thorough investigation on 8-oxoG(+) deprotonation reaction by density functional theory (DFT). Our calculation results show that the pK(a) values of active protons in 8-oxoG(+) are 0.23 (N7-H), 3.42 (N1-H), 5.91 (N2-H-a) and 6.43 (N2-H-b), respectively, where the deviation is about 0.32. This result rationalizes previous inconsistent experimental results. The energy barriers for N7-H transfer of 8-oxoG(+) toward the direction of O6 and O8 are 11.7 and 13.1 kJ mol(-1), respectively, and that for N1-H is 28.5 kJ mol(-1), indicating that the N1-H of 8-oxoG(+) could act as a potential deprotonation site. Then, to clearly illustrate the mechanism for 8-oxoG(+) deprotonation of N7-H, 15 other hydration models were built by assessing systematically the effects of explicit water molecules added in the hydration model. It is found that these three water molecules placed around N7-H, O6/O8 of 8-oxoG(+) as well as the one located in the second hydration shell are necessary for describing the process of 8-oxoG(+) deprotonation from N7-H, where the protonated water cluster plays an important role in the process of proton release from 8-oxoG(+) to the first hydration shell. Moreover to introduce an additional water molecule located in the negative direction of proton transfer (around O8/O6) is helpful for estimating the energy barrier of proton transfer accurately. These results would provide an in-depth perspective to understand the important role of 8-oxoG in DNA oxidative damage.