Rotation about the C6-O6 bond in O6-methylguanine: the syn and anti conformers can be of similar energies in duplex DNA as estimated by molecular modeling techniques.
Rotation about the C6-O6 bond in O6-methylguanine: the syn and anti conformers can be of similar energies in duplex DNA as estimated by molecular modeling techniques.
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O6-甲基鸟嘌呤中 C6-O6 键的旋转：根据分子建模技术估计，双链体 DNA 中的顺式和反式构象异构体可能具有相似的能量。
DOI：
10.1093/carcin/12.9.1693
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发表时间：
1991
期刊：
影响因子：
4.7
通讯作者：
Loechler,EL
中科院分区：
文献类型：
--
作者：
Loechler,EL
O6-甲基鸟嘌呤(O6MeGua)通常被认为是由致癌甲基化试剂形成的最重要的诱变前损伤，因此其结构和作用机制受到了极大的关注。O6MeGua中的甲基可能有两种构象：一种是甲基相对于嘌呤的N(1)位置是合成的，指向螺旋，破坏氢键；第二种是甲基相对于嘌呤的N1位置是对映体，指向主槽。核磁共振结果表明，当在双链DNA中与胸腺嘧啶配对时，观察到了Syn-O6MeGua，而在X射线衍射研究中，观察到了与胸腺嘧啶配对的反O6MeGua。在这里，分子模拟/计算化学被用来评估这种明显的差异。还研究了[N6-甲基腺嘌呤(N6MeAde)]，因为它与O6MeGua是等电子的，而且关于它的能量有更多的信息。计算表明，Syn-N6MeAde在小分子中是有利的；然而，计算出反构象的比例为˜7%，与实验测定的值(4-12%)符合得很好。相反，N6MeAde的反构象被计算为有利于在双链DNA中，这与用核磁共振和X射线衍射技术实验观察到的一致。N6MeAde的计算结果与实验测定结果的一致性表明，该方法是合理的。]对于O6MeGua，计算了小分子˜_(103)的同步/反比。在双链DNA中，syn(O6MeGua)被认为是有利的，但反构象的能量比˜高1千卡/摩尔。O6MeGua是否占主导地位可能取决于序列背景和环境因素。O6MeGua和N6MeAde之间的比较为令人费解的观察提供了一个理论基础，即O6MeGua似乎是真核细胞中的细胞毒性损伤，但不是原核细胞。
O6-Methylguanine (O6MeGua) is generally regarded as the most important premutagenic lesion formed from carcinogenic methylating agents, so its structure and mechanism of action have received considerable attention. Two conformations for the methyl group in O6MeGua are possible: in one the methyl group issynwith respect to the N(1)-position of the purine, points into the helix, and disrupts hydrogen bonding potential; in the second the methyl group isantiwith respect to the N1-position of the purine, and points into the major groove.Syn-O6MeGua has been observed when paired with thymine in duplex DNA as determined by NMR, whileanti-O6MeGua has been observed when paired with thymine in X-ray diffraction studies. Herein, molecular modeling/computational chemistry is used to evaluate this apparent discrepancy. [N6-Methyladenine (N6MeAde) was also studied, because it is isoelectronic with O6MeGua, and because more information is available about its energetics.Syn-N6MeAde is computed to be favored in small molecules; however, the fraction of theanti-conformer is computed to be ˜7%, which agrees well with experimentally determined values (4–12%). In contrast, theanticonformation for N6MeAde is calculated to be favored in duplex DNA, which is consistent with what has been observed experimentally using both NMR and X-ray diffraction techniques. The agreement between the calculated and experimentally determined results with N6MeAde suggest that the methods are reasonable.] For O6MeGua, asyn/antiratio of ˜103is computed for small molecules. In duplex DNA,syn(O6MeGua is computed to be favored, but theanti-conformer is ˜ 1 kcal/mol higher in energy. Whethersyn- oranti-O6MeGua predominates may depend upon sequence context, as well as environmental factors. The comparison between O6MeGua and N6MeAde suggests a rationale for the puzzling observation that O6MeGua appears to be a cytotoxic lesion in eukaryotic, but not prokaryotic, cells.