Mimicking Reverse Turns with Cyclic Tetrapeptides

Chemical mimics of the reverse turn structures in proteins have proven useful as therapeutics. This thesis describes the investigation of cyclic tetrapeptides (CTPs) which are found to be rigid and synthetically feasible turn mimics. CTPs rigidity were probed computationally and a few test examples made by solid phase peptide synthesis and then characterized by NOESY NMR. All reverse turns in the Protein Data Bank (PDB) were analyzed to determine conformational clustering based on the orientation of the four Calpha-Cbeta bonds. Combining the residues of glycine, L and D alanine, L and D proline, L and D N-methyl-alanine, and L and D pipecolic acid yielded a computational library of CTPs that mimicked over half the turns in the PDB, as determined by overlap of less than 0.65A RMSD with the four Calpha-Cbeta bonds of each of 9 turn clusters.