Reverse turns are common motifs in protein structure and have been implicated as recognition elements in crystal structures of antibody- peptide complexes and in structure-activity studies of the peptide hormones, angiotensin II, bradykinin, GnRH (gonadotrophin releasing hormone, LHRH), and somatostatin. 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 have recently demonstrated the feasibility of electrochemical methods for preparing bicyclic turn mimics from simple dipeptide precursors, Xxx-Pro. In addition, our theoretical studies suggest that dipeptides consisting of NMe amino acids of alternating chirality should be strong turn-inducers. 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 tetrapeptide into which turn mimics will be incorporated. Detailed structural analyses (NMR, FTIR, CD) will be used to characterize the populations of turn structures in these model peptides. Turn mimics will be next be incorporated into a well-characterized turn.containing peptide (Gramicidin S) 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 both the simple model system and the gramicidin S analogs. In the final phase, detailed information about the turn mimics derived from the earlier studies will be applied to two experimental systems - understanding the conformational link between bradykinin agonist/antagonists and bradykinin itself, and the design of a peptide with the ability to recognize RNA structural motifs.
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