Significant effects of phosphorylation on relative stabilities of DNA and RNA sugar radicals:: Remarkably high susceptibility of H-2′ abstraction in RNA
Significant effects of phosphorylation on relative stabilities of DNA and RNA sugar radicals:: Remarkably high susceptibility of H-2′ abstraction in RNA
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DOI：
10.1021/jp060331j
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发表时间：
2006-07-13
影响因子：
3.3
通讯作者：
Guo, Qing-Xiang
中科院分区：
文献类型：
--
作者：
Li, Min-Jie;Liu, Lei;Guo, Qing-Xiang
核酸自由基在DNA和RNA损伤中的作用在不了解描述产生这些自由基中的每一个的能量成本的C-H键强度的情况下不能被正确地理解。然而，以前的理论研究不同的核酸自由基的相对能量是不完全令人信服的，主要是因为使用过于简化的模型化合物。本研究选择核苷3 '，5'-二磷酸作为DNA和RNA的模型化合物，同时考虑了核碱基和磷酸化的影响。用新发展的ONIOM-G3B3方法计算了模型化合物中所有碳水化合物C-H键的气相键离解能和液相键离解自由能。发现单阴离子磷酸盐基团（OPO 3H-）是比OH基团好1.3 kcal/mol的自由基稳定基团，而中性磷酸盐基团（OPO 3H 2）是比OH差4.4 kcal/mol的自由基稳定基团。由于这些原因，从脱氧核糖核苷酸和核糖核苷酸的H-提取的相对热力学敏感性根据磷酸化状态和磷酸基团所携带的电荷而变化很大。值得注意的是，无论磷酸化状态和磷酸基团携带的电荷如何，核糖核苷酸中C2 '-H键的键解离自由能都比所有其他C-H键的键解离自由能低5 - 6kcal/mol。这解释了先前的实验发现，RNA的辐射损伤主要通过H-2 '处的H-提取发生。模型研究表明，2 '-OH和3-磷酸基团之间的氢键相互作用的强度从核糖核苷3'，5 '-二磷酸到其C2'自由基应显著增加。增强的氢键稳定了C2 '自由基，使得RNA的C2'-H键非常容易被H-夺取。
The roles of nucleic acid radicals in DNA and RNA damage cannot be properly understood in the absence of knowledge of the C-H bond strengths depicting the energy cost to generate each of these radicals. However, previous theoretical studies on the relative energies of different nucleic acid radicals are not fully convincing mainly because of the use of oversimplified model compounds. In the present study we chose nucleoside 3 ', 5 '-bisphosphates as model compounds for DNA and RNA, in which the effects of both the nucleobase and phosphorylation were taken into consideration. Using the newly developed ONIOM-G3B3 methods, we calculated the gas-phase bond dissociation enthalpies and solution-phase bond dissociation free energies of all the carbohydrate C-H bonds in the model compounds. It was found that the monoanionic phosphate group (OPO3H-) was a better radical stabilization group than the OH group by 1.3 kcal/mol, whereas the neutral phosphate group (OPO3H2) was a significantly worse radical stabilization group than OH by 4.4 kcal/mol. Due to these reasons, the relative thermodynamic susceptibility of H-abstraction from deoxyribonucleotides and ribonucleotides varied considerably depending on the phosphorylation state and the charge carried by the phosphate groups. Strikingly, the bond dissociation free energy of C2 '-H in ribonucleotides was dramatically lower than that of all the other C-H bonds by 5-6kcal/mol regardless of the phosphorylation state and the charge carried by the phosphate group. This explained the previous experimental finding that radiation damage of RNA occurs mainly via H-abstraction at H-2 '. A model study suggested that the strength of the hydrogen bonding interaction between the 2 '-OH and 3-phosphate groups should dramatically increase from ribonucleoside 3 ',5 '- bisphosphate to its C2 ' radical. The strengthened hydrogen bonding stabilized the C2 ' radical, rendering the C2 '-H bond of RNA extraordinarily vulnerable to H-abstraction.