Reverse turns are common motifs in protein structure and have been implicated as recognition elements in structure-activity studies of the peptide hormones, angiotensin II, bradykinin, GnRH, somatostatin, and many others. Despite many efforts to design turn mimetics, their application to SAR studies of peptides has been relatively infrequent due in part to complicated multistep syntheses which limit the incorporation of sidechain groups into the turn mimic. We propose to continue the design and synthesis of novel reverse turn mimics derived from simple dipeptides. Computational tools will be used to predict the reverse-turn propensities of potential mimetics prior to their synthesis. These tools will be experimentally validated using a simple model, gramicidin S, into which turn mimics will be incorporated. Detailed structural analyses (NMR, FTIR, CD) will be used to characterize the populations of turn structures in this model peptide. Turn mimics will be incorporated into well-characterized turn-containing peptides followed by extensive structural characterization to assess the local geometry at the mimic and any conformational effects that propagate from the turn mimetic along the peptide backbone. The effect of the local environment on turn propensity for each mimic-solvent, adjacent residue type, peptide length-will be probed in the gramicidin S analogs. In the final phase, detailed information about the turn mimics derived from the earlier studies will be applied to understanding the conformational link between bradykinin agonist/antagonists and bradykinin itself through use of receptor mutants.
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