新型荧光DNA修饰碱基的分子设计及其分子识别能力的理论研究

The design and development of fluorescent base analogues is one of the research hotspots in nucleic acid, primarily motivated by the fact that these analogues have important and widespread applications in DNA sequencing, DNA hybridization detection, antibody immune analysis, disease diagnosis, as well as anti-cancer drug analysis. The present work focuses on the structure modification of natural DNA bases with the aim of designing several base analogues that have improved and novel properties. The structures, electronic properties, stabilities, and electronic spectroscopy properties of them as well as the new DNA duplexes will be studied. The molecular recognition abilities of their electronic spectroscopy on local biological environments, including the base pairing, base stacking, solvents, metal ions, gold nanoclusters, etc., will be clarified, and the molecular recognition criterion will be build. Based on the results mentioned above, the potential applications of these newly designed base analogues in study of base mispair, group interactions, and molecular recognition would be explored. Finally, the effects of different modification strategies on the spectroscopies of DNA bases and the relationships between the structures and property would be summarized. The study conclusions were anticipated to be helpful on the design and synthesis of fluorescent base analogues experimentally.

荧光核酸碱基类似物在DNA自动测序、探测DNA杂化、抗体免疫分析、疾病诊断和抗癌药物分析等方面具有重要而广泛地应用，因此设计和开发具有良好荧光活性的碱基类似物是核酸研究领域的热点课题之一。本项目围绕核酸修饰的相关问题，拟对天然碱基进行改良修饰，设计若干新型碱基类似物，并利用理论化学方法探讨其结构性质、电子性质、稳定性、电子光谱性质以及新型DNA链的相关性质；阐明其电子光谱对生物微环境（包括配对模式、堆积模式、溶剂效应、金属离子和纳米金团簇等）的响应识别能力，建立相应的分子识别标度，从而考查新设计碱基在研究碱基错配、基团作用和分子识别方面的可能性；总结修饰碱基与天然碱基在光谱性质上的差异和不同修饰策略所带来的影响，获得其结构与性质参数之间的内在相关性，为荧光核酸碱基类似物的实验设计、合成及应用提供一些科学依据和理论参考。

荧光碱基类似物的设计和开发是核酸研究的热点课题之一，本项目围绕核酸碱基修饰的相关问题，基于对天然碱基和几类新型碱基类似物光谱性质研究的初步进展，利用增加稠合芳香环及助色团策略对天然碱基进行改良修饰，设计得到了一系列新型尺寸扩大碱基（包括“苯扩环”异噻唑RNA碱基、“噻吩”三环嘌呤类似物和“乙烯”基三环噻吩嘌呤类似物）。采用量子化学方法表征了它们的结构性质、电子性质及稳定性；研究了它们的光谱性质，对它们的若干低能电子激发态进行了详细解析，表征了其激发态几何结构和电子性质；澄清了碱基配对、溶剂效应（水合程度）、糖环等环境因素对单体电子光谱的影响规律。同时对部分新型碱基与纳米金团簇和金属离子之间的相互作用机制及规律进行了研究。以上研究可以为荧光核酸碱基类似物的实验设计、合成及应用提供一定的科学依据和参考。