5R,6S-Tg立体异构体稳定构型的理论研究

Theoretical study on the stable conformation of 5R,6S-Tg stereoisomers

胸腺嘧啶二醇(Thymine glycol,Tg)是最常见的DNA氧化损伤,人体基因组内含有数千个Tg损伤.Tg对DNA聚合酶有强的阻断,可能导致细胞死亡、癌症等严重后果.一旦生成,Tg就以两对顺反立体异构体混合物的形式存在,修复酶对Tg的修复表现出立体选择性.在所有的异构体中,5R,6S-Tg数量最多.NMR实验表明5R,6S-Tg 5-CH_(3)可能存在轴向或赤道两种不同构象,但是5R,6S-Tg最稳定构象依然存在争论.基于碱基水平的理论研究表明5R,6S-Tg 5-CH_(3)取向为轴向时最稳定.然而,本研究在核苷水平的计算表明,5-CH_(3)取向为赤道时最稳定,高精度的簇耦合理论CCSD(T)/6-311++G(d,p)对结果进行了验证.进一步的分析表明,分子内氢键和氧孤电子对之间的π-π共轭协同作用稳定了5R,6S-Tg的赤道构象.

Thymine glycol(Tg)is the most common DNA oxidative damage,and there are thousands of Tg damages in human genome.Tg has a strong blocking effect on DNA polymerase and may lead to serious consequences such as cell death and cancer.Once Tg is generated,it exists in the form of a mixture of two cis-trans stereoisomers,and the repair enzyme exhibits stereoselectivity for Tg repair.Among all isomers,5R,6S-Tg with the highest quantity.NMR study have shown that the 5-CH_(3) of 5R,6S-Tg may have two different conformations,axial or equatorial,however,the most stable conformation of 5R,6S-Tg is still debated.Studies based on the base level indicate that the 5R,6S-Tg is most stable when the 5-CH_(3) is axial,however,our calculations at the nucleoside level indicate that the 5R,6S-Tg with 5-CH_(3) in equatorial is the most stable conformation,CCSD(T)/6-311++G(d,p)calculation confirms the results.Further analysis showed that the synergistic effect of intramolecular hydrogen bonding andπ-πconjugation stabilized the equatorial conformation of 5R,6S-Tg.