Hybrid Peptides: Expanding the β Turn in Peptide Hairpins by the Insertion of β‐, γ‐, and δ‐Residues

Abstract The β turn segment in designed peptide hairpins has been expanded by the insertion of β‐, γ‐ and δ‐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‐β 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 β hairpin conformations in methanol by the observation of key diagnostic nuclear Overhauser effects. Boc‐Leu‐Val‐Val‐ D Pro‐δ‐Ava‐Leu‐Val‐Val‐OMe ( 4 ) adopts a β 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 α–α segment is expanded to C 11 , C 12 , and C 13 turns in α–β, α–γ, and α–δ segments, respectively. The crystal structures of Piv‐ L Pro‐β 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 β hairpins in the cases of peptides 2 and 3 . Accommodation of ω‐amino acids into the turn segments is achieved by the adoption of gauche conformations around the backbone CC bonds.