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‐NH 2 ] 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 m M , and that its backbone conformation is superimposable on corresponding hairpins containing the D Pro‐Gly (literature) and Aib‐ D Ala (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 D Pro‐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. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 746–753, 2007. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com