DNA碱基甲基化对碱基间相互作用和DNA构象以及DNA-蛋白质结合的影响

Effects of DNA Bases Methylated on Interactions between Base-Pairs,the DNA Conformations and Protein bound DNA

比较了采用量子化学从头算方法(ab initio)计算的非甲基化-甲基化DNA碱基间的氢键和堆积作用.结果表明,碱基甲基化损伤减弱了碱基间的氢键作用能,但使堆积作用能增大.应用自然键轨道(NBO)理论,分析了采用M062x/6-31+G(d,p)算法优化的C5-甲基胞嘧啶(C5-MeC)和O6-甲基鸟嘌呤(O6-MeG)与非甲基化碱基间的氢键结构.NBO分析揭示,甲基插入O6-G,改变了授受体作用方式,产生的空间障碍使cis-O6MeG…C的N1(G)…HN4(C)的距离增大,nN1(G)的电荷迁移能力减小,导致cis-O6MeG…C的氢键作用能小于anti-O6MeG…C.采用分子动力学方法 (MD)模拟了IBRCA基因启动子区富CpG序列中12mer的寡聚体,分析了CpG甲基化(mCpG)对DNA双链体构象的影响.结果表明,不同位点的mCpG,对DNA双链体平面内的碱基对结构基本没有影响,但CpG段的堆积结构参数以及DNA大小沟的宽度和深度发生了不同程度的改变.还进一步分析了mCpG对K50型同源域转录因子PITX2与DNA相互作用的影响.得到的结论与文献基本一致.

This paper compares hydrogen bonding with stacking interaction energies between un - and meth-ylated DNA bases calculated by quantum chemistry ab initio method. The results show that methylation lesion of DNA bases weaken the energies of hydrogen bond interactions and strengthen stacking interactions. The hydrogen bonding structures between C^5 -methylation cytosine （C^5 -MeC） or O^6 -methylation guanine（ O^6 - MeG） and unmethylation bases, optimized at the M062x/6 - 31 ＋ G （ d, p） level, were explored by Natural Bond orbital （NBO） theory. NBO analysis reveals that steric hindrances caused by an insert of a methyl into O^6 -- G largen space between N^1 （ C ） and N2H2 （ G）, so that hydrogen bonding interaction energies of c/s - O^6MeG…C is lower than that of anti - O^6MeG…C. In addition, 12 mer oligomers of CpG - enrich sequence of promotor region in gene Brcal were simulated and effects of CpG methylated （mCpG） on conformations of DNA duplexs were analyzed by molecular dynamic （MD） method. With analysis of simulated results for four DNA duplexes,it is found that, when different sit cytosines were methylated in CpG - enrich sequence, pa-rameters of stacking structure, width and depth of major and minor groove of mCpG steps present different changes. The paper further discusses effects of mCpG on DNA binding protein. Analysis conclusions are basi-cally accord with references.