Dr. Kemp has a pioneering program in construction of small molecule models that permit better understanding of the chemistry and structure of peptides and proteins. This project, which is in the Organic and Macromolecular Chemistry Program, should lead to better understanding of biological interactions at the molecular level which could lead to very important industrial consequences. Current theories of protein folding postulate that regions in the amino acid sequence that have a high probability of assuming specific secondary structures act as nucleation sites for further folding. Moreover, many interactions of receptors with peptide hormones or proteins with posttranslational modifying enzymes appear to involve beta-turns at the site of recognition. In this work, analogs of amino acids are to be synthesized which are more rigid than the natural amino acids and which stabilize the several types of turns, pleated sheets and alpha-helices when attached to peptide chains. The emphasis is on demonstrating that the turn, sheet, and helix templates that have been prepared actually assume the proposed structures when attached to simple peptides. A variety of tests for conformations of these simple hybrids are proposed to establish this latter point. Second generation templates that can be used to test further hypotheses will be synthesized and studied. In subsequent studies the proven templates for secondary structure are to be incorporated semisynthetically into proteins at key folding regions. In a related effort, analogs of some of the peptide hormones are to be prepared, using the turn-templates as structural elements. With these studies, the object is to enhance the binding at the receptor site as well as to protect the hormone analog from proteolysis. The long-range objectives of this study are thus the construction of hybrid peptides and proteins with properties that are not realizable with the natural amino acids.
