含铜核酸酶与DNA相互作用的理论研究-物理化学专业论文.docxVIP

摘要 摘要 万方数据 万方数据 弱；TPA 配体及其衍生物中，连接区长度的不同直接导致了其核酸酶相应的 DNA 结合能力不同。本部分工作为设计新型含铜核酸酶提供了理论指导。 2. 本部分通过分子动力学模拟方法对六个配体结构相似的含铜核酸酶与 DNA 的结合能力及切割活性进行了研究。这六个核酸酶分子分别是 Cu(E1)2+, Cu(E2)2+, Cu(E3)2+, Cu(E4)2+, Cu(E5)2+和 Cu(E6)2+。分析结果表明，除 Cu(E4)2+ 外其它分子都结合在 DNA 小沟内。自由能及氢键分析结果表明，六个含铜核酸 酶分子与 DNA 的 结 合 顺 序 为 Cu(E5)2+ ＞ Cu(E6)2+ ＞ Cu(E2)2+ ＞ Cu(E4)2+ ＞ Cu(E1)2+＞Cu(E3)2+，与实验结果一致。与此同时，模拟结果表明，与含铜核酸 酶进行相互作用后的 DNA 与标准 B-DNA 的螺旋参数频率分布有巨大的差异， 这些差异导致 DNA 的转录和复制受到抑制。此外，RDF 分析结果表明研究的六 个核酸酶分子（Cu(E5)2+, Cu(E2)2+, Cu(E6)2+ , Cu(E1)2+, Cu(E3)2+和 Cu(E4)2+）的 DNA 切割活性依次降低，与实验结果相符。本部分工作为我们从分子水平上理 解相似配体的含铜核酸酶有不同的核酸酶活性提供了有价值的理论信息。 关键词： DNA， 含铜核酸酶， 分子对接， 分子动力学模拟， MM_PBSA II Abst Abstract Abstract In recent decades, copper nucleases have drawn considerable attention in relation to its diversity and stability of the structure and high activity in biological probe, genetic engineering and anticancer drugs. Copper nucleases have shown DNA cleavage activities under physiological conditions in biological systems since they can attack the sugar or base of DNA, resulting in diseased DNA stand scission. Since the discovery of the first copper nuclease, a very large number of copper nucleases have been synthesized and tested for their DNA affinities and DNA cleavage abilities, which are potential to become candidates for genetic drugs. Acting as anticancer drugs or specific genetic modification agent in actual applications, it is particularly important for copper nuclease to improve the corresponding DNA binding affinity and specific cleavage. Therefore, the key issue in the design of copper nucleases is the DNA binding affinity and cleaving specificity. However, studies of binding models of copper nucleases to DNA and interaction mechanism of nuclease with DNA are very limited to date. It is a difficult subject to understand essentially the important information mentioned above, unless more detail information at the molecular level can be obtained. In this thesis, we systematically studied the binding affinities of c