Supramolecular Chemistry of beta-Sheets

β-折叠的超分子化学

• 批准号: 0213533
• 负责人: James Nowick
• 金额: $ 38.3万
• 依托单位: University of California-Irvine
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0213533&HistoricalAwards=false
• 关键词: Supramolecular; Chemistry; beta; Sheets

This proposal aims to elucidate factors involved in edge-to-edge interactions between beta- sheets and to learn how to control this important mode of protein interaction, which is involved in protein dimerization, protein-protein recognition, and protein aggregation. The proposal builds upon an exciting discovery by the Principal Investigator under NSF award CHE-9813105 ("Molecular Templates for Creating Artificial Protein Structures") of a molecular template that induces beta-sheet folding and interactions when incorporated into peptides. This molecular template is constructed as a composite of two amino acids. One of these, Orn, is natural although not routinely found in proteins; the other, Hao, was invented by the Principal Investigator and his students under the prior NSF support. The Orn-Hao composite is easily incorporated into peptides using standard peptide synthesis techniques. Peptides containing the Orn-Hao composite dimerize in a fashion similar to that of certain beta-sheet proteins. The current proposal will study the dimerization of peptides containing the Orn-Hao composite and learn how to control the dimerization process through a series of experiments. The earlier experiments will focus upon optimizing the structure and folding of peptides containing the Orn-Hao composite, while the later experiments will focus upon learning how to use specific interactions to control the dimerization. All of these studies will rely heavily upon organic synthesis, peptide synthesis, NMR titration, and NMR NOE methods. The intellectual merit of this work is that interactions between beta-sheets are widespread and important, yet the molecular basis for these interactions is not well understood. The proposed work explores creative and original concepts, by using small chemical model systems to address this fundamental and important biological problem. One special merit of using these small chemical model systems, instead of larger proteins, is that these systems can be prepared easily and used to evaluate hypotheses very rapidly. Another special merit of these model systems is that they will be able to be prepared in other laboratories, thus enabling other researchers to use them to test their own ideas about protein folding and interactions.With this Award, the Organic and Macromolecular Chemistry Program (OMC) will support the research of Professor James Nowick of the University of California- Irvine. Professor Nowick's work is expected to generate valuable basic scientific knowledge with important biomedical implications. In addition, this proposal will have broader impacts through the training of students and the development of human resources. Undergraduate, graduate, and postdoctoral students working on this project will be trained to perform cutting-edge research in the laboratory and will also learn to effectively communicate their results to others by presenting their work in seminars, at meetings, and through publications. Many of these well-trained students will contribute to the US scientific endeavor and the economy as researchers in the pharmaceutical industry.

该提案旨在阐明β-折叠之间边对边相互作用的因素，并了解如何控制这种重要的蛋白质相互作用模式，其涉及蛋白质二聚化，蛋白质-蛋白质识别和蛋白质聚集。该提案建立在NSF奖CHE-9813105（“用于创建人工蛋白质结构的分子模板”）下的主要研究者的令人兴奋的发现基础上，该分子模板在并入肽中时诱导β折叠和相互作用。该分子模板被构建为两种氨基酸的复合物。其中之一，Orn，是天然的，尽管在蛋白质中并不常见;另一个，Hao，是由首席研究员和他的学生在先前的NSF支持下发明的。Orn-Hao复合物使用标准肽合成技术容易地掺入肽中。含有Orn-Hao复合物的肽以类似于某些β折叠蛋白的方式二聚化。目前的提案将研究含有Orn-Hao复合物的肽的二聚化，并通过一系列实验了解如何控制二聚化过程。早期的实验将专注于优化含有Orn-Hao复合物的肽的结构和折叠，而后期的实验将专注于学习如何使用特定的相互作用来控制二聚化。所有这些研究都将严重依赖于有机合成、肽合成、NMR滴定和NMR NOE方法。这项工作的智力价值是β-折叠之间的相互作用是广泛和重要的，但这些相互作用的分子基础还没有得到很好的理解。拟议的工作探索创造性和原创性的概念，通过使用小化学模型系统来解决这个基本而重要的生物学问题。使用这些小的化学模型系统，而不是较大的蛋白质的一个特殊优点是，这些系统可以很容易地制备，并用于评估假设非常迅速。这些模型系统的另一个特殊优点是，它们将能够在其他实验室制备，从而使其他研究人员能够使用它们来测试他们自己关于蛋白质折叠和相互作用的想法。有了这个奖项，有机和大分子化学计划（OMC）将支持加州-欧文大学的James Nowick教授的研究。 Nowick教授的工作预计将产生具有重要生物医学意义的宝贵的基础科学知识。此外，这项建议将通过培训学生和开发人力资源产生更广泛的影响。从事该项目的本科生，研究生和博士后学生将接受培训，在实验室中进行尖端研究，并将学习通过在研讨会，会议和出版物中展示他们的工作来有效地向他人传达他们的结果。这些训练有素的学生中的许多人将作为制药行业的研究人员为美国的科学奋进和经济做出贡献。