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 alphaalpha-dialkyl amino acids in stabilizing helical structures in synthetic peptides is presented, with an emphasis on work carried out in the authors laboratory. Alpha-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. Beta-hairpin design has been approached by exploiting the tendency of 'prime turns' to nucleate hairpin formation. The use of nucleating (D)Pro-Gly segments has resulted in the generation of several well characterized beta-hairpin structures, including the crystallographic observation of beta-hairpin in a synthetic apolar octapeptide. Extensions of this approach to three stranded beta-sheets and larger structures containing multiple (D)Pro-Gly segments appear readily possible.