9.6nm高密度脂蛋白结构与功能的透射电子显微镜与分子动力学模拟研究

项目名称： 9.6nm高密度脂蛋白结构与功能的透射电子显微镜与分子动力学模拟研究

项目编号： No.11504287

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 数理科学和化学

项目作者： 张磊

作者单位： 西安交通大学

项目金额： 24万元

中文摘要： 软物质物理研究是物理科学通向生命科学的桥梁。生物大分子的结构与功能研究是这座桥梁最重要的基石之一。当今心血管疾病是人类健康的头号杀手，因此与之直接相关的高密度脂蛋白成为近年来这方面的热点研究对象。盘状9.6nm高密度脂蛋白是脂蛋白中承上启下的一种关键蛋白，仅含有磷脂和两个apoA-I蛋白；了解该蛋白的结构与功能，将会极大地提高对脂蛋白整个家族的认识。然而由于高密度脂蛋白的分子量小、结构易变等特性，确定其结构仍然是该领域内公认的难题。在本项目中，申请人提出应用针对脂蛋白优化的负染色电镜方法、冷冻电镜条件和电子断层成像重构技术以及分子动力学模拟等手段，来研究9.6nm高密度脂蛋白及其复合物的二维形貌和高分辨三维结构特征，进而确定其分子模型，得到apoA-I与磷脂的作用机制，揭示高密度脂蛋白的生长和变化机理，为从源头上解决心血管疾病提供关键基础，为软物质物理研究在生物大分子方面的深入提供新思路。

中文关键词： 生物大分子；结构与功能；透射电子显微镜；脂蛋白；负染色

英文摘要： Soft matter physics builds a bridge between physics and biology. Structure and function research of biological macromolecules is one of the most important foundation stones of this bridge. As cardiovascular diseases (CVD) have become the No.1 killer of human health, in recent decades high-density lipoprotein (HDL), which directly relates to human CVD, is becoming a hot research target in this field. Discoidal 9.6nm HDL (140-240 kDa) is a critical intermediate protein of HDL family, and it only contains phospholipids and two apoA-I molecules. It will greatly improve the knowledge of HDL family by studying the structure and function of 9.6nm HDL. However, due to its small molecular weight and dynamic conformations, it is still an open challenge to determining its structures. In this proposal, the applicant proposed to use electron cryo-microscopy, negative-staining electron microscopy, which were specially optimized for lipoproteins, individual-particle electron tomography, and molecular dynamics simulation to study the structure and function of 9.6nm HDL and its complex, by investigating their two-dimensional morphologies and high-resolution three-dimensional reconstructions; then the atom model of this HDL will be defined, and the interaction mechanisms between apoA-I and phospholipids will be obtained; finally the mechanisms of growth and conformational changes of HDL will be revealed. All these results will provide critical information for curing CVD from the sources, and will definitely bring new thoughts for deepening the researches of soft matter physics in biomacromolecular fields.

英文关键词： Biological Macromolecules;Structure and Function;Transmission Electron Microscopy;Lipoprotein;Negative-staining