Supramolecular Chemistry of beta-Sheets

这项建议旨在阐明β-折叠之间边到边相互作用所涉及的因素，并学习如何控制这一重要的蛋白质相互作用模式，这一模式涉及蛋白质二聚、蛋白质-蛋白质识别和蛋白质聚集。这项提议是建立在国家科学基金会奖CHE-9813105(“用于创建人造蛋白质结构的分子模板”)下的首席研究员的一项令人兴奋的发现的基础上，该发现发现了一种分子模板，当将其结合到多肽中时，可以诱导β-折叠和相互作用。该分子模板是由两个氨基酸组成的复合体。其中一种名为Orn，是天然的，尽管通常不存在于蛋白质中；另一种名为Hao，是由首席研究员和他的学生在先前NSF的支持下发明的。使用标准的多肽合成技术可以很容易地将Orn-Hao复合材料并入多肽中。含有Orn-Hao复合体的多肽以类似于某些β-折叠蛋白的方式二聚化。目前的方案将研究含有Orn-Hao复合材料的多肽的二聚化，并通过一系列实验学习如何控制二聚化过程。早期的实验将专注于优化含有Orn-Hao复合材料的多肽的结构和折叠，而后来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。所有这些研究都将在很大程度上依赖于有机合成、肽合成、核磁共振滴定和核磁共振NOE方法。这项工作的学术价值在于，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被很好地理解。这项拟议的工作探索了创造性和原创性的概念，通过使用小型化学模型系统来解决这一基本和重要的生物学问题。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非常快速地评估假说。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，有机和高分子化学计划(OMC)将支持加州大学欧文分校的詹姆斯·诺维克教授的研究。诺维克教授的工作有望产生具有重要生物医学意义的有价值的基本科学知识。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。参与该项目的本科生、研究生和博士后将接受在实验室进行前沿研究的培训，并将学习通过在研讨会、会议和出版物上展示他们的工作来有效地与他人交流他们的成果。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努力和经济做出贡献。

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.