初生态盘状高密度脂蛋白（HDL）是预防和治疗心血管疾病的关键靶标。由于分子量小、结构动态性强，HDL的结构与功能以及两者之间微观物理机理的研究依然是领域内公认的难题和亟待解决的重要科学问题。在本项目中，我们拟采用针对脂蛋白优化的负染色方法、冷冻电镜技术、单粒子电子断层成像技术和分子动力学模拟等手段，研究几种关键盘状HDL的三维动态结构及其调控脂类输运的微观物理机理。首先解构多种状态下盘状HDL及其复合物的三维电子密度图，研究HDL从无脂到饱含磷脂状态的物理生长过程，定位关键氨基酸位点；然后利用分子建模方法建立各种状态的分子模型，揭示其多态和多功能的物理成因；最后应用分子动力学模拟深入研究载脂蛋白A-I与磷脂动态相互作用的物理过程，阐明HDL动态结构与载脂功能的微观物理机理。为从源头上理解心血管疾病的成因奠定基础，为新型靶向药物的设计提供指导，为物理学在生物大分子方面的深层次应用提供新思路。

Nascent discoidal high-density lipoprotein (HDL) is the key target to prevent and cure cardiovascular diseases. Due to small molecular weights and dynamic conformations, it is still an open challenge and important scientific question to determining HDL’s structures and functions and the microscopic physical mechanisms between its structures and functions. In this project, the applicant proposes to use optimized negative-staining electron microscopy, which were specially optimized for lipoproteins, electron cryo-microscopy, individual-particle electron tomography and molecular dynamics simulations, to study the three-dimensional dynamic structures and the microscopic physical mechanisms of several key nascent discoidal HDLs and their complexes. By reconstructing the three-dimensional electron density maps of discoidal HDLs and their complexes, the physical growth process will be studied and key amino acid sites will be located. Then by employing molecular modelling methods, the atomic models of HDLs under different status will be built, and the physical origins of HDLs’ multiple structures and functions will be defined. Finally, molecular dynamics simulations will be used to deeply research the physical process of the dynamic interaction of apoA-I and lipids, and the microscopic physical mechanisms of HDLs’ dynamic structures and lipid-transferring functions will be discovered. All of these results will lay the foundation of understanding the origins of CVD from the source, and will provide guidance of designing novel targeted drugs, and will also definitely bring new thoughts for deepening the application of physics in biomacromolecular research fields.