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 pKa values of active protons in 8-oxoG˙+ are 0.23 (N7–H), 3.42 (N1–H), 5.91 (N2–Ha) and 6.43 (N2–Hb), 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.