Stereochemical control of peptide folding

Stereochemically constrained amino acid residues that strongly favour specific backbone conformations may be used to nucleate and stabilize specific secondary structures in designed peptides. An overview of the use of αα-dialkyl amino acids in stabilizing helical structures in synthetic peptides is presented, with an emphasis on work carried out in the authors laboratory. α-Aminoisobutyric acid (Aib) and related achiral homologs facilitate stable helix formation in oligopeptides as exemplified by a large number of crystal structure determinations in the solid state. The ability to design conformationally rigid helical modules has been exploited in attempts to design structurally well characterized helix-linker-helix, using potential nonhelical linking segments. β-Hairpin design has been approached by exploiting the tendency of 'prime turns' to nucleate hairpin formation. The use of nucleating DPro-Gly segments has resulted in the generation of several well characterized β-hairpin structures, including the crystallographic observation of β-hairpin in a synthetic apolar octapeptide. Extensions of this approach to three stranded β-sheets and larger structures containing multiple DPro-Gly segments appear readily possible