Wang Yinghui, Ma Lei, Wei Simin
College of Science, Chang'an University, Xi'an 710064, China.
State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Co-Construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, Shaanxi University of Chinese Medicine, Xianyang 712083, China.
ACS Omega. 2024 Dec 13;9(51):50730-50741. doi: 10.1021/acsomega.4c08956. eCollection 2024 Dec 24.
Due to the lower oxidation potential than natural nucleic acid bases, one-electron oxidation of DNA is usually funneled into the direction of intermediates for oxidized DNA damage like 8-oxo-7,8-dihydroadenine (8-oxoA) leading to a radical cation, which may undergo facile deprotonation. However, compared to the sophisticated studies devoted to natural bases, much less is known about the radical cation degradation behavior of an oxidized DNA base. Inspired by this, a comprehensive theoretical investigation is performed to illuminate the deprotonation of 8-oxoA radical cation (8-oxoA) in both free and encumbered context by calculating the p value and mapping the energy profiles. The calculative p values of active protons in free 8-oxoA follow the order: N7-H < N9-H < N6-H1< N6-H2, suggesting the preference of proton departure in free 8-oxoA. To further illustrate the preferred site and mechanism for 8-oxoA deprotonation, energy profiles are constructed to distinguish the possibility from that of all active protons in both contexts. The results show distinctly that 8-oxoA mainly suffers from the loss of proton from N9 due to the lowest energy barrier but deprotonates N7-H in real DNA as the connection of N9 and ribose. The energy barriers for the deprotonation of N7-H from 8-oxoA in free and encumbered contexts are 1.5 and 1.3 kcal/mol, respectively, indicating a fast deprotonation reaction. It is more interestingly that the N9-H proton transfer (PT, toward N3) to adjacent water follows a stepwise fashion rather than a one-step approach as previously reported. Furthermore, the PT behavior of free N9-H toward O8 is dramatically influenced by base pairing T, where it is localized at neighboring water without further PT to adjacent water in free 8-oxoA but migrated directly to adjacent water in the 8-oxoA:T base pair. And the deprotonation of N6-H2 in 8-oxoA:T is disturbed as the PT to O4 of the pairing T base is inhibited. It is warmly anticipated that these results could provide an in-depth perspective to understand the important role of 8-oxoA in mutation.
由于氧化电位低于天然核酸碱基，DNA的单电子氧化通常朝氧化DNA损伤中间体的方向进行，如8-氧代-7,8-二氢腺嘌呤（8-氧代A），从而产生一个自由基阳离子，该阳离子可能容易发生去质子化。然而，与针对天然碱基的深入研究相比，我们对氧化DNA碱基的自由基阳离子降解行为了解得少得多。受此启发，我们进行了一项全面的理论研究，通过计算pKa值并绘制能量分布图，以阐明8-氧代A自由基阳离子（8-氧代A⁺）在自由和受限环境中的去质子化情况。自由8-氧代A中活性质子的计算pKa值顺序为：N7-H < N9-H < N6-H1 < N6-H2，这表明自由8-氧代A中质子离去的偏好顺序。为了进一步说明8-氧代A去质子化的优先位点和机制，我们构建了能量分布图，以区分两种环境中所有活性质子去质子化的可能性。结果清楚地表明，8-氧代A主要由于最低的能垒而从N9失去质子，但在实际DNA中，由于N9与核糖的连接，8-氧代A从N7-H去质子化。在自由和受限环境中，8-氧代A中N7-H去质子化的能垒分别为1.5和1.3千卡/摩尔，这表明去质子化反应很快。更有趣的是，N9-H质子转移（PT，朝向N3）到相邻水的过程遵循分步方式，而不是如先前报道的一步方式。此外，自由N9-H向O8的PT行为受到碱基配对T的显著影响，在自由8-氧代A中，它定位在相邻水上，不会进一步向相邻水进行PT，但在8-氧代A:T碱基对中直接迁移到相邻水。并且8-氧代A:T中N6-H2的去质子化受到干扰，因为向配对T碱基的O4的PT受到抑制。热切期待这些结果能够为理解8-氧代A在突变中的重要作用提供深入的视角。
