This research is being supported by the Organic Synthesis Program. The synthesis of the complex polypeptides and proteins that occur in natural systems requires an understanding of how nature controls the structure and properties of these complex molecules. This work should help to clarify these factors and lead to the design of new biologically active compounds to be used in agriculture and medicine. Most theories of protein folding postulate that local regions of the protein's amino acid sequence have a higher than average tendency to fold or coil to assume sheet or helical structures that can then act as nucleation sites for later folding steps involving nonlocal interactions. Hitherto, studies of helix formation have been hampered by the failure of most short polypeptides to assume detectible sheet or helix structure. In the work, helix nucleation sites in the form of rigid groupings of three amides or amide surrogates are to be synthesized and bonded to short polypeptide sequences. With these hybrids, the role of chain length, amino acid composition, charge at the nucleation site, and solvation will be followed by a variety of high field proton nuclear magnetic resonance techniques and by circular dichroism. In addition to the N-terminal helix nucleating template that has been developed during the preceding project period, C-terminal nucleation templates will be synthesized and studied, and the geometry of the N-terminal template will be refined. The aims of these studies include estimation of the stabilizing effect of the template on adjacent helical polypeptide, determining the geometrical features of the growth of short helices, and the degree to which the helix-forming tendency of amino acid residues is independent of enviroment. The long range objective of this study is the design of protein analogs with predictable folding properties, using the concurrently developed thiol capture method for protein synthesis to generate `chimeric' small proteins that contain covalently incorporated nucleation templates.
