G-四链体DNA构型转变的NMR溶液结构及分子机制研究

G-四链体（G4）DNA由富含鸟嘌呤的DNA序列折叠形成。人体基因的G4-DNA序列达到70多万条，其拓扑构型丰富多样，它们在生物体内动态存在，参与很多重要生理和病理过程。早期研究受圆二色等光谱方法的限制只观察到G4-DNA构型转变现象，一直无法回答“G4构型为什么转变、如何转变的分子机制及对应的构效关系”等关键科学问题。研究核酸动态结构最有效的手段是多维核磁（NMR）技术，因此，本项目拟以核酸NMR技术为手段、金属铂配合物为诱导剂，结合离子种类或浓度变化、细胞模拟拥挤环境等调控手段，用NMR方法解析G4形成与转变的动态溶液结构，获得G4转变的新颖结构变化及稳态、亚稳态结构信息，探索转变过程稳态和亚稳态的热动力学及对应生物功能变化，总结调控条件与规律，阐明G4构型转变的分子机制和构效关系，为揭示G4的形成演变、G4与疾病的关系、G4靶向小分子设计提供结构基础和科学依据。

G-quadruplex (G4) DNA is formed by the folding of guanine-rich DNA sequences. There are about 700,000 G4-DNA forming sequences in human genomes, which can form a variety of topological conformations. They exist dynamically in organisms and participate in many important physiological and pathological processes. Limited by the circular dichroism and other spectral methods, the early researches only observed the phenomenon of G4-DNA conformational switch. Thus, it is unable to answer the key scientific questions such as "why the G4 conformation switch, how the G4 transform its conformation, and what is the molecular mechanism and the corresponding structure-activity relationship". The most effective method to explore the dynamic structures of nucleic acids is the multidimensional nuclear magnetic (NMR) technology. As a result, this project plan to use the nucleic acid NMR technology to investigate the dynamic process of G4 forming and structural changing induced by platinum complexes, and further explore the influences of ion concentration change and cell simulation crowded environment. We will obtain the dynamic solution NMR structures of G4-DNA during it forming and switching conformations, and then investigate the novel structural changes of the metastable state. After that, we will explore the thermal dynamics and corresponding biological function changes between the steady and metastable states, and summarize the regulation law. Finally, we will clarify the molecular mechanisms and the structure-activity relationships of G4 configuration changes, which can provide the structural and scientific basis for revealing the formation and evolution of G4, the relationship between G4 and diseases, and the design of G4-targeting small molecules.