The Structure and Assembly of Peptide Aggregates

描述（由申请人提供）：蛋白质和肽的聚集是许多疾病的原因，包括阿尔茨海默病和帕金森病。了解肽聚集机制的细节是在分子水平上理解这些疾病的先决条件。本项目将结合生物物理技术描述朊病毒肽和人γ - d -晶体蛋白的结构和组装机制，重点关注三个具体目标：(1)利用同位素编辑红外光谱（IR）、差示扫描量热法和肽设计与修饰相结合，剖析朊病毒肽在溶液中形成β -片的机制；(2)结合红外光谱、电子显微镜和原子力显微镜研究朊病毒肽纤维的形态、链排列和形成动力学；(3)利用同位素编辑红外技术研究γ - d -晶体蛋白中的蛋白质聚集。这些研究将导致对聚集过程的全面描述，从单个多肽的初始构象变化到肽聚集的早期阶段，再到大纤维沉淀物的形成。这种对聚集过程的全面描述将为在分子水平上提高对许多疾病的认识奠定基础，并为开发新的药物策略开辟道路。

DESCRIPTION (provided by applicant): The aggregation of proteins and peptides is responsible for a number of diseases, including AIzheimer's and Parkinson's diseases. An understanding of the details of peptide aggregation mechanisms is prerequisite to understanding these diseases on the molecular level. This project will use a combination of biophysical techniques to describe the structure and assembly mechanism of a prion peptide and human gamma-D-crystallin, focusing on three specific aims: (1) dissecting the mechanism of beta-sheet formation by prion peptides in solution, using a combination of isotope-edited infrared (IR) spectroscopy, differential scanning calorimetry, and peptide design and modification; (2) exploring the morphology, strand alignment, and formation kinetics of prion peptide fiber through a combination of IR, electron microscopy, and atomic force microscopy; and (3) applying the isotope-edited IR technique to the study of protein aggregation in gamma-D-crystallin proteins. These studies will result in a comprehensive description of the aggregation process, from the initial conformational changes of individual polypeptides to the early stages of peptide aggregation to the formation of large fibrous precipitates. Such a thorough description of the aggregation process will lay a foundation for an improved understanding of many diseases at the molecular level, and also open the way for the development of new pharmaceutical strategies.