Hybrid Peptides: Expanding the \beta Turn in Peptide Hairpins by the Insertion of \beta-, \gamma-, and \delta-Residues

The \beta turn segment in designed peptide hairpins has been expanded by the insertion of \beta-, \gamma- and \delta amino acids at the i+2 position. The model octapeptides Boc-Leu-Phe-Val-$^D$Pro-$Ac_6c$-Leu-Phe-Val-OMe (1), Boc-Leu-Phe-Val-$^D$Pro-$\beta^3$-$Ac_6c$-Leu-Phe-Val-OMe (2),and Boc-Leu-Phe-Val-$^D$Pro-Gpn-Leu-Phe-Val-OMe (3) have been shown to adopt \beta hairpin conformations in methanol by the observation of key diagnostic nuclear Overhauser effects. Boc-Leu-Val-Val-$^D$dPro-\delta-Ava-Leu-Val-Val-OMe (4) adopts a \beta hairpin conformation in crystals; this is stabilized by three cross-strand hydrogen bonds as demonstrated by X-ray diffraction. The canonical $C_{10}$ turn in an \alpha–\alpha segment is expanded to $C_{11}$, $C_{12}$,and $C_{13}$ turns in \alpha–\beta, \alpha–\gamma, and \alpha–\delta segments,respectively. The crystal structures of Piv-$^L$Pro-$\beta^3$-$Ac_6c$-NHMe (5) and Boc-$Ac_6c$-Gpn-$Ac_6c$-OMe (6) reveal intramolecularly hydrogen-bonded $C_{11}$ and $C_{12}$ conformations, respectively. Computer modeling of octapeptide sequences that contain centrally positioned hybrid-turn segments, by using turn parameters derived from the structures of peptides 5 and 6,establishes the stereochemical acceptability of the \beta hairpins in the cases of peptides 2 and 3. Accommodation of $\omega$-amino acids into the turn segments is achieved by the adoption of gauche conformations around the backbone $C - C$ bonds