生物膜界面神经退化型疾病相关蛋白质聚集动力学的和频光谱研究

The molecular mechanism of neurodegenerative disease-associated protein aggregation plays a key role in revealing the formation and development of neurodegenerative diseases. However, lacking effective tools to characterize protein structure and dynamics in the process of neurodegenerative disease-associated protein aggregation on biomembrane, the molecular mechanism of neurodegenerative disease-associated protein aggregation at biomembrane surface remains substantially unexplored. In this project, a highly sensitive femtosecond broadband sum-frequency generation vibrational spectroscopy with simultaneous measurement of multiple polarization combinations will be applied to investigate the dynamics of neurodegenerative disease-associated protein (such as amyloid-beta, alpha-synuclein and prions) aggregation at biomembrane surface, as well as the transient changes of the protein conformation and biomembrane structure during the aggregation. On this basis, we will correlate protein conformation changes and aggregation dynamics. This correlation may help to reveal the nature of protein misfolding at molecular level, as well as understand the influence of protein conformation on aggregation dynamics. The results from this project will provide an in-depth insight into the nature and rules of neurodegenerative disease-associated protein aggregation process, and reveal the molecular mechanism of the formation and development of neurodegenerative diseases. Finally, it may provide new ideas for the early diagnosis and the development of therapeutic drugs for neurodegenerative diseases.

神经退化型疾病相关蛋白质聚集的分子机制是揭示神经退化型疾病产生和发展的关键。因缺乏表征生物膜上神经退化型疾病相关蛋白质聚集过程中蛋白质分子结构和动力学的有效手段，目前对其分子机制还知之甚少。本项目拟利用高灵敏、多偏振组合同时测量的飞秒宽带和频光谱系统，以生物膜界面上的神经退化型疾病相关蛋白质（Aβ蛋白、α突触核蛋白以及朊蛋白）为对象，系统研究神经退化型疾病相关蛋白质与生物膜作用动力学过程，以及聚集过程中蛋白质分子构象与膜结构的瞬态变化。在此基础上，将蛋白质分子构象变化与聚集动力学过程关联起来，从分子水平上揭示神经退化型疾病相关蛋白质错误折叠机理，理解蛋白质分子结构如何影响聚集动力学行为，从而更加深入地认识神经退化型疾病相关蛋白质聚集过程的本质与规律，进而揭示神经退化型疾病发生、发展的分子机理，最终为疾病的早期诊断和治疗药物开发提供新思路。

本项目顺利完成了三年执行期的研究内容和研究目标。构建了界面蛋白质结构特征谱学标识，这样的特征谱学标识将在界面蛋白质的结构表征中发挥重要作用。我们利用高灵敏、多偏振组合同时测量的飞秒宽带和频光谱系统结合飞秒时间分辨和频光谱系统研究了神经退行型疾病相关蛋白质在生物膜界面的聚集动力学过程和超快动力学过程。获得了一系列原创成果，主要包括酸性条件可以抑制人胰岛淀粉样多肽在生物膜界面向纤维转变；蛋白质-水的耦合作用调节膜蛋白酰胺I振动模式的非谐性；磷脂电荷可以诱导Aβ蛋白错误折叠，Aβ蛋白折叠过程中酰胺骨架驱动侧链，水合化作用驱动Aβ蛋白向纤维转变；疏水匹配介导TDP43与不同疏水长度磷脂膜的作用。这些研究结果将进一步加深人们对神经退行型疾病相关蛋白质错误折叠机制的理解。

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