Continuing studies are proposed in the area of sequenceconformation relationships in polypeptides. We will use synthetic model peptides and will examine their conformations by several physical methods, with nuclear magnetic resonance serving as the principal tool. The various peptide sequences to be studied in the next project period are of intermediate-length (5 to 40 residues) and are selected from native systems wherein structure and function appear to be directly influenced by conformational behavior of short linear polypeptide sequences. Each case therefore explores a facet of the fundamental question of importances of local interactions in proteins and peptides. Furthermore, in each case reverse turns play a critical role as conformational determinants. The conformational properties of the different sequences will be examined in a variety of environments that are illustrative of biological microenvironments and are likely to favor adoption of particular conformations. Specifically, we propose to: (1) extend our basic work on reverse turns, with emphasis on: a) importance of sequence and of environment on likelihood of gamma turns; and b) key interactions of turns in hydrophobic environments (for example, specific interactions with water); (2) investigate the conformational behavior of geneticallycharacterized """"""""foldons"""""""" from the bacteriophage P22 tail spike endorhamnosidase; (3) test a conformational hypothesis put forth by Berzofsky and coworkers for immunodominance of particular protein sequences in activation of T cells; (4) test the hypothesis that exons encode polypeptide sequences with structural roles in the gene product; (5) determine conformations of several conformationallyconstrained analogues of gonadotropinreleasing hormone (GnRH), compare these results to molecular dynamics calculations and use the findings to propose a bioactive conformation of GnRH itself; (6) design and test potential inhibitors of C3/5 convertase, a critical protease in the complement cascade.
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