Supramolecular Chemistry of Amyloidogenic Peptides

有了这个奖项，化学系的生命过程化学计划正在资助加利福尼亚大学欧文分校的James Nowick教授利用化学合成来创建模型系统，这些系统以与更复杂的生物分子相同的方式组装，从而作为蛋白质聚集的模型系统。 由肽和蛋白质形成的称为淀粉样蛋白组装体的分子组装体与多种疾病有关，例如阿尔茨海默病、额颞痴呆、帕金森病和2型糖尿病。该项目旨在了解更多关于这些淀粉样蛋白低聚物的结构。 生成的化学模型系统具有可以形成晶体的优点，从而可以通过X射线晶体学精确地确定低聚物的结构。通过确定这些化学模型系统的结构，研究人员将深入了解由相关肽和蛋白质形成的分子组装体。该项目将通过研究中获得的知识，研究生和本科生的培训，K-12教育推广以及对STEM教育的贡献来实现更广泛的影响。协助该项目的研究生和本科生将接受培训价值的跨学科培训。 大量的K-12学生正在通过UCI化学推广计划的目标。PI将继续通过UCI的OpenChem倡议，通过教学和为公众创建视频内容，为美国和全球层面的STEM教育做出贡献。Nowick研究小组已经开发出一种新的策略来阐明由淀粉样蛋白生成肽形成的低聚物的结构：将肽并入大环化合物中，并使用单个N-甲基基团来防止不受控制地聚集成纤维。所得的大环β折叠肽组装形成定义明确的低聚物，并且相当大部分的肽形成适合于X射线晶体学的晶体。该方法将用于阐明来自蛋白质tau、蛋白质α-突触核蛋白和胰岛淀粉样多肽（IAPP，胰淀素）的淀粉样蛋白生成肽的寡聚体的结构。所形成的低聚物的结构将通过X射线晶体学以原子分辨率确定，并且低聚物的晶体学结构将通过尺寸排阻色谱法和其他技术如NMR光谱法与溶液中的低聚状态相关联。这些寡聚体的生物学性质与天然淀粉样蛋白生成肽和蛋白质的生物学性质之间的关系将通过斑点印迹测定来评估。这些研究旨在更好地理解寡聚体序列和三维结构之间的关系，以及这些对稳定性和生物学特性的影响。

With this award, the Chemistry of Life Processes Program in the Division of Chemistry is funding Professor James Nowick of the University of California-Irvine to utilize chemical synthesis to create model systems that assemble in the same fashion as the more complex biomolecules, and thereby serve as model systems for the aggregation of proteins. Molecular assemblies known as amyloid assemblies formed by peptides and proteins have been implicated in a variety of diseases, such as Alzheimer's disease, frontotemporal dementias, Parkinson's disease, and type 2 diabetes. This project seeks to learn more about the structures of these amyloid oligomers. The chemical model systems being generated have the advantage that they can form crystals, allowing the structures of the oligomers to be determined with exquisite precision by X-ray crystallography. By determining the structures of these chemical model systems, the researchers will gain insights into the molecular assemblies formed by associated peptides and proteins. This project will achieve broader impact through the knowledge gained in the research, the training of students at the graduate and undergraduate level, K-12 educational outreach, and contributions to STEM education. Graduate students and undergraduates who assist in the project will receive training value cross-disciplinary training. A large number K-12 students are being targeted through the UCI Chemistry Outreach Program. The PI will continue to contribute to STEM education on the US and global level through UCI's OpenChem Initiative, by teaching and creating video content for the public. The Nowick research group has developed a new strategy to elucidate the structures of oligomers formed by amyloidogenic peptides: incorporating the peptides into macrocycles and using a single N-methyl group to prevent uncontrolled aggregation to fibrils. The resulting macrocyclic beta-sheet peptides assemble to form well-defined oligomers, and a sizeable fraction of the peptides form crystals suitable for X-ray crystallography. This approach will be used to elucidate the structures of oligomers from amyloidogenic peptides derived from the protein tau, the protein alpha-synuclein, and the islet amyloid polypeptide (IAPP, amylin). The structures of the oligomers that form will be determined at atomic resolution by X-ray crystallography, and the crystallographic structures of the oligomers will be correlated with the oligomerization state in solution by size-exclusion chromatography and other techniques such as NMR spectroscopy. The relationship between the biological properties of these oligomers and those of natural amyloidogenic peptides and proteins will be assessed by dot-blot assays. These studies aim to provide a better understanding of the relationship between oligomer sequence and three dimensional structure, and the implications of these upon stability and biological properties.