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(6)c-Leu-Phe-Val-OMe (1), Boc-Leu-Phe-Val- (D)Pro-beta(3)-Ac(6)c-Leu- Phe-Val-OMe (2), and Boc-Leu-Phe-Val- (D)Pro-Gpn-Leu-Phe-Val-OMe (3) have been shown to adopt (3 hairpin conformations in methanol by the observation of key diagnostic nuclear Overhauser effects. Boc-Leu-Val-Val- (D)Pro-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(6)c-NHMe (5) and Boc-Ac(6)c-Gpn-Ac(6)c-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.