Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions,The Journal of Physical Chemistry A

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Theoretical Insights on the Inefficiency of RNA Oxidative Damage under Aerobic Conditions
The Journal of Physical Chemistry A ( IF 2.7 ) Pub Date : 2017-12-28 00:00:00 , DOI: 10.1021/acs.jpca.7b10711
Shuang Zhao ₁ , Leif A. Eriksson ₂ , Ru-bo Zhang ₁

Affiliation

Oxidative damage to RNA has been linked to change or loss of RNA function and development of many human age-related diseases. However, knowledge on the nature of RNA oxidative damage is relatively limited. In this study, oxidative damage to RNA is investigated under anaerobic and aerobic conditions by exploring the properties and reactions of 5-hydroxyl-2′-uridin-6-yl and its peroxyl diastereoisomers in the RNA strand, respectively. Selective addition of OH to the nucleic base from the 5′-end is studied at the molecular level for the first time, explaining the large number of the 5S-isomer available for further reactions. Our results provide clear evidence that the efficiency of C2′–H2′ bond activation in the peroxyl isomers is lower than in the carbon radical species. An exception is observed for the isomer cis-(5S,6R)-A1, whose internucleotidyl H2′-abstraction barrier is far smaller than that in the corresponding C6-yl radical. However, analysis of the equilibrium species distribution reveals that the amount of cis-(5S,6R)-A1 is very small among the peroxyl diastereoisomers, and hence the resulting products from direct strand scission should be a less important component in RNA oxidative damage. The species with maximum distribution is the cis-(5S,6R)-B1 isomer, which is derived from cis-(5S,6R)-A1 and has a moderate intranucleotidyl H2′-abstraction barrier. More importantly, the reaction is mildly exothermic. These results show that the main fraction of the intranucleotidyl H2′-abstraction intermediates can be formed from the cis-(5S,6R)-B1 isomer. The absolute reduction potentials, the hydrogen atom binding energies, and the key structural parameters of the C6-peroxyl species are used to understand the diverse reactivity of the cis-(5S,6R) diastereoisomers toward the C2′–H2′ bonds activation. The present study shows that in addition to the selectivity of the OH radical addition, there is a strong correlation between the conformation of the modified uracil base and its reactivity in RNA oxidative damage.

中文翻译：

有氧条件下RNA氧化损伤效率低下的理论见解。

RNA的氧化损伤与RNA功能的改变或丧失以及许多人类与年龄有关的疾病的发展有关。然而，关于RNA氧化损伤的性质的知识相对有限。在这项研究中，分别通过研究RNA链中5-羟基-2'-尿素-6-基及其过氧非对映异构体的性质和反应，研究了在厌氧和需氧条件下对RNA的氧化损伤。首次在分子水平上研究了从5'端向核酸碱基的OH选择性加成，这解释了可用于进一步反应的大量5 S-异构体。我们的结果提供了明确的证据，表明过氧异构体中C2'–H2'键活化的效率低于碳自由基。观察到异构体的异常顺式-（5 S，6 R）-A1，其核苷酸间H2'-抽象性阻隔性远小于相应的C6-基团中的阻隔性。然而，对平衡物种分布的分析表明，在过氧非对映异构体中，顺式-（5 S，6 R）-A1的量非常小，因此直接链断裂产生的产物在RNA氧化中的重要性应该较低损害。具有最大分布的物种是顺式-（5 S，6 R）-B1异构体，其衍生自顺式-（5 S，6 R）-A1，并具有中等的核苷酸内H2'-抽象屏障。更重要的是，该反应是温和放热的。这些结果表明，可以由顺式-（5 S，6 R）-B1异构体形成核苷酸内H2'提取中间体的主要部分。使用绝对还原电位，氢原子结合能和C6-过氧物种的关键结构参数来了解顺式-（5 S，6 R）向C2'–H2'的非对映异构体键活化。本研究表明，除了OH自由基加成的选择性外，修饰的尿嘧啶碱基的构象与其在RNA氧化损伤中的反应性之间还存在很强的相关性。

更新日期：2017-12-28

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