Li Min-Jie, Liu Lei, Wei Kai, Fu Yao, Guo Qing-Xiang
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China.
J Phys Chem B. 2006 Jul 13;110(27):13582-9. doi: 10.1021/jp060331j.
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 5-6 kcal/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.
如果不了解描述生成这些自由基的能量成本的C-H键强度，就无法正确理解核酸自由基在DNA和RNA损伤中的作用。然而，以前关于不同核酸自由基相对能量的理论研究并不完全令人信服，主要是因为使用了过于简化的模型化合物。在本研究中，我们选择核苷3',5'-二磷酸作为DNA和RNA的模型化合物，其中同时考虑了碱基和磷酸化的影响。使用新开发的ONIOM-G3B3方法，我们计算了模型化合物中所有碳水化合物C-H键的气相键解离焓和溶液相键解离自由能。结果发现，单阴离子磷酸基团（OPO3H-）比羟基（OH）是更好的自由基稳定基团，相差1.3千卡/摩尔，而中性磷酸基团（OPO3H2）比羟基是明显更差的自由基稳定基团，相差4.4千卡/摩尔。由于这些原因，脱氧核糖核苷酸和核糖核苷酸中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带电荷的不同而有很大差异。引人注目的是，无论磷酸化状态和磷酸基团所带电荷如何，核糖核苷酸中C2'-H的键解离自由能比所有其他C-H键都低5-6千卡/摩尔。这解释了先前的实验发现，即RNA的辐射损伤主要通过H-2'处的H提取发生。一项模型研究表明，2'-OH和3-磷酸基团之间的氢键相互作用强度应从核苷3',5'-二磷酸到其C2'自由基显著增加。增强的氢键稳定了C2'自由基，使RNA的C2'-H键极易受到H提取的影响。
