Supramolecular Chemistry of beta-Sheets

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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.