Dimers of 9-aminoacridine linked via the 9-amino group with polymethylene chains, termed diacridines, are known to bisintercalate into DNA when the linker comprises 6 or more methylene units. There are no literature reports of crystal or NMR solution structures for bisintercalated diacridine-DNA complexes, and the issue of the structure of the C6 ([CH2 ]n linker where n = 6) diacridine complex remains unresolved. Previously, based on simple geometric considerations, it was proposed that C6 diacridine could only span a single base pair, which requires that its bifunctional reaction violates the widely-observed "neighbor exclusion principle" where bound intercalators are separated by at least 2 base pairs. Here we have explored the structure of diacridine-DNA complexes using unrestrained molecular dynamics in explicit solvent using the parmbsc0 forcefield in AMBER14. We studied the C4 to C8 dimers, intercalated via both the minor and major DNA grooves, to a variety of nucleotide sequences. We find that C6, C7, and C8 diacridine are able to form 2 base pair bisintercalated complexes from either groove, whereas the C4 and C5 homologues cannot. We conclude that C6 diacridine does have the capacity to bisintercalate without violating neighbor exclusion, and that the previous proposed binding model needs revision.

中文翻译：

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双吖啶与 DNA 结合的分子动力学模拟：表明 C6 双吖啶可以跨越两个碱基对进行双嵌入

已知通过 9-氨基与多亚甲基链连接的 9-氨基吖啶二聚体，称为二吖啶，当接头包含 6 个或更多亚甲基单元时，会双嵌入 DNA。没有关于双嵌入双吖啶-DNA 复合物的晶体或 NMR 溶液结构的文献报道，C6（[CH2]n 接头，其中 n = 6）双吖啶复合物的结构问题仍未解决。此前，基于简单的几何考虑，有人提出 C6 双吖啶只能跨越单个碱基对，这要求其双功能反应违反了广泛观察到的“邻域排除原则”，即结合的嵌入剂至少被 2 个碱基对隔开。在这里，我们使用 AMBER14 中的 parmbsc0 力场在显式溶剂中使用不受限制的分子动力学探索了双吖啶-DNA 复合物的结构。我们研究了 C4 到 C8 二聚体，通过 DNA 小沟和大沟插入到各种核苷酸序列中。我们发现 C6、C7 和 C8 双吖啶能够从任一凹槽形成 2 个碱基对双嵌入复合物，而 C4 和 C5 同源物则不能。我们得出结论，C6 双吖啶确实具有在不违反邻域排斥的情况下进行双嵌入的能力，并且之前提出的结合模型需要修改。C8 双吖啶和 C8 双吖啶能够从任一凹槽形成 2 个碱基对双嵌入复合物，而 C4 和 C5 同源物则不能。我们得出结论，C6 双吖啶确实具有在不违反邻域排斥的情况下进行双嵌入的能力，并且之前提出的结合模型需要修改。C8 双吖啶和 C8 双吖啶能够从任一凹槽形成 2 个碱基对双嵌入复合物，而 C4 和 C5 同源物则不能。我们得出结论，C6 双吖啶确实具有在不违反邻域排斥的情况下进行双嵌入的能力，并且之前提出的结合模型需要修改。