The specific aims of the proposed research are the syntheses of (1) bicyclic peptides with varying cavity sizes to serve as model cation-binding moities, (2) cyclic peptides with oxazoline or thiazole groups, (3) linear peptides having amino acid sequences of a transmembrane portion of bacteriorhodopsin, and (4) """"""""leader"""""""" sequences of one or more membrane proteins. The bicyclic peptides should approximate more closely than previous models the ion-binding sites of metalloenzymes. Investigations are planned of both the specificity and quantitative aspects of ion binding. The cyclic peptides incorporating heterocyclic ring systems relate to recently discovered naturally-occurring cyclic peptides. In all four categories listed above, the peptides synthesized will be used for conformational investigations, both in solution and ultimately in lipid bilayer systems such as vesicles. In some cases it will be necessary to synthesize the peptides with NMR labels such as 19F, 13C, and 2H, which will allow conformational determinations of both greater precision and with the capability of solving peptide structures of greater complexity. The compounds prepared under this grant will be used for conformational investigations under another on-going NIH research grant. The main physical techniques to be used for solution conformational investigations will be NMR spectroscopy and circular dichroism. The long-term objectives of this research are to increase our understanding of the mode of action of proteins and the relationships between the structure of proteins and their biological functions. The importance to health of understanding both the specificity of cation-binding to peptides and proteins and the modes of ion transport in cells and tissues is well-documented in biochemical and medical literature.
