Theoretical insight into 7,8-dihydrogen-8- oxoguanine radical cation deprotonation
Theoretical insight into 7,8-dihydrogen-8- oxoguanine radical cation deprotonation
复制标题
7,8-二氢-8-氧代鸟嘌呤自由基阳离子去质子化的理论见解
DOI：
10.1039/d1nj01653a
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发表时间：
2021
影响因子：
3.3
通讯作者：
王英辉
中科院分区：
文献类型：
--
作者：
魏思敏;张振华;刘世军;王英辉
7,8-二氢-8-氧代鸟嘌呤 (8-oxoG) 因其在 DNA 复制中通过 GC → TA 颠换而收集而引起了分析人员的广泛关注；特别是，由于与鸟嘌呤相比氧化还原电位较低，8-oxoG 被认为是最终的“正空穴”汇，DNA 的氧化集中到这个方向。因此，人们在 8-oxoG 的单电子氧化和随后的去质子化反应方面做出了大量的努力。然而，之前的研究仍然存在一些不一致的结果，8-oxoG˙+的去质子化机制在很大程度上仍然难以捉摸。在此，我们利用密度泛函理论（DFT）对8-oxoG˙+去质子化反应进行了深入研究。我们的计算结果表明，8-oxoG˙+中活性质子的pKa值分别为0.23（N7–H）、3.42（N1–H）、5.91（N2–Ha）和6.43（N2–Hb），偏差约为0.32。这一结果合理化了之前不一致的实验结果。 8-oxoG˙+的N7-H向O6和O8方向转移的能垒分别为11.7和13.1 kJ mol−1，N1-H的能垒为28.5 kJ mol−1，表明8-oxoG˙+的N1-H可以作为潜在的去质子化位点。然后，为了清楚地说明 N7–H 8-oxoG˙+ 去质子化的机制，通过系统评估水化模型中添加的显式水分子的影响，建立了其他 15 个水化模型。研究发现，位于N7–H、8-oxoG˙+的O6/O8周围的这三个水分子以及位于第二水化壳中的水分子对于描述8-oxoG˙+从N7–H去质子化的过程是必要的，其中质子化水簇在8-oxoG˙+质子释放到第一水化壳的过程中起着重要作用。此外，在质子传递负方向（O8/O6周围）引入额外的水分子有助于准确估计质子传递的能垒。这些结果将为理解 8-oxoG 在 DNA 氧化损伤中的重要作用提供深入的视角。
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.