面向老年痴呆症-淀粉状蛋白纤维结构解析的固体NMR新方法的研究

Alzheimer's disease has a serious impact on human health, and brings a huge economic burden to the society. The research on the formation process and the structure of amyloid fibrils, a characteristic symptoms in Alzheimer's disease, together with the development of therapeutic drugs for Alzheimer's disease becomes a hot spot. This program, targeting at the revelation of the structure of amyloid fibrils, will focus on the development of a variety of new solid-state NMR characterization methods, in order to take full advantages of the strong magnetic field and high spinning speed. We are going to develop new solid-state NMR methods with low RF power, broadband excitation and high accuracy for high-field/ultra-high-field and high-spinning-speed/ultra-high-spinning-speed, to obtain the short-distance 13C-13C correlation and long-distance 13C-13C correlation and the exact distance of long range 13C-15N.The new solid-state NMR characterization methods we want to develop, will help to obtain a three-dimensional structure of the turn regions in the amyloid fibrils with more accuracy, which would provide a solid theoretical basis for the prevention and treatment of Alzheimer's diseases and development of new drugs.

老年痴呆症严重影响人类的健康，并给社会带来巨大的经济负担。研究老年痴呆症中具有特征性症状的淀粉样蛋白纤维的形成过程及纤维结构并开发治疗性药物成为一个热点。本课题将以淀粉样蛋白纤维的结构研究这一科学问题为目标，开发多种新型的固体NMR表征新技术，以充分发挥强磁场与高转速的优势。本课题将开发(超)高场与(超)高转速条件下的低功率、宽频激发和高准确性的固体核磁共振新方法来获取13C-13C的近程和远程相关信息以及13C-15N之间的远程距离信息。本课题所开发的固体NMR表征新技术，有助于获得更加准确的淀粉样蛋白的无规区域三维结构，因此可以为老年痴呆症疾病的防治及新药开发提供坚实的理论基础。

蛋白质的错误折叠会导致老年痴呆症；而固体核磁共振是研究蛋白质的有力工具。蛋白质常见的研究元素有2H、13C、14N和15N等。本课题主要开发了2H的宽频激发方法、14N的直接采样消除基线不平、基于overtone倍频双量子的14N HMQC直接检测与复合脉冲的宽频激发、基于Overtone的13C-14N距离信息获取、15N-15N远距离相关的检测等研究。我们还研究了可以缩短采样时间的Covariance方法其采样次数和信噪比之间的关系。最后我们还使用“面向蛋白质”开发的CODEX序列和EXCHANGE序列对固体高分子电解质的整体链运动和局部链段运行进行了详细的表征与分析。本课题所开发的固体NMR表征新技术，有助于获得蛋白的三维结构信息或动力学信息，也有助于其他高分子和有机化合物体系的表征与研究。