Nonstereogenic α-aminoisobutyryl-glycyl dipeptidyl unit nucleates type I′ β-turn in linear peptides in aqueous solution

The use of α,α-disubstituted amino acids represents a valuable strategy to exercise conformational control in peptides. Incorporation of the nonstereogenic α-aminoisobutyryl-glycyl (Aib-Gly) dipeptidyl sequence into i + 1 and i + 2 positions of an acyclic peptide sequence, originally designed and investigated by Gellman and coworkers, [H-Arg-Tyr-Val-Glu-Val-Yyy-Xxx-Orn- Lys-Ile-Leu-Gln-NH₂] nucleates a stable [2:4] left-handed type I′ β-turn in water. NMR spectra show that this newly designed β-hairpin does not aggregate in water up to a concentration of ∼ 1 mM, and that its backbone conformation is superimposable on corresponding hairpins containing the DPro-Gly (literature) and Aib-DAla (this work) sequences. The Aib-Gly turn-inducer sequence eliminates complications because of cis-trans isomerization of Zzz-Pro bonds, and constitutes an attractive alternative to the proteogenic Asn-Gly and nonproteogenic DPro-Gly motifs previously suggested as turn-inducer sequences. These design principles could be exploited to prepare water-soluble β-hairpin peptides with robust structures and novel function.