Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures
Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures
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DOI：
10.1093/nar/gkq1362
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发表时间：
2011-05-01
影响因子：
14.9
通讯作者：
Wilson, W. David
中科院分区：
文献类型：
--
作者：
Hunt, Rebecca A.;Munde, Manoj;Wilson, W. David
杂环二脒是具有抗寄生虫特性的化合物，其靶向动质体 DNA 小沟。这些化合物的作用机制尚不清楚，但可能涉及 DNA 结构的拓扑变化。在本研究中，我们开发了一种基于聚丙烯酰胺凝胶电泳的筛选方法，以确定杂环二脒对四个小沟靶序列的拓扑效应：AAAAA、TTTAA、AAATT 和 ATATA。 AAAAA 和 AAATT 序列具有最大的固有弯曲，而 TTTAA 和 ATATA 序列相对较直。化合物结合引起的变化是序列依赖性的，但一般来说，对 AAAAA 和 AAATT 的拓扑效应与对 TTTAA 和 ATATA 的效应相似。总共评估了 13 种具有各种结构差异的化合物对 DNA 的拓扑变化。所有化合物都会降低 ATATA 序列的移动性，这与小沟宽度的减小以及相对直的 DNA 弯曲到小沟中是一致的。 TTTAA 也有类似的效果，但通常较小。本质上弯曲的 AAAAA 和 AAATT 序列具有更窄的小凹槽，在结合时具有较小的迁移率变化，这与取决于化合物结构的弯曲的增加或减少一致。
Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure.