Hybrid peptides: Expanding the 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-^DPro-Ac₆c-Leu-Phe-Val-OMe (1), Boc-Leu-Phe-Val-^DPro-β³-Ac₆c-Leu-Phe-Val-OMe (2), and Boc-Leu-Phe-Val-^DPro-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-^DPro-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 C₁₀ turn in an α-α segment is expanded to C₁₁, C₁₂, and C₁₃ turns in α-β, α-γ, and -α-δ segments, respectively. The crystal structures of Piv-^LPro-β³-Ac₆c-NHMe (5) and Boc-Ac₆c-Gpn-Ac₆c-OMe (6) reveal intramolecularly hydrogen-bonded C₁₁ and C₁₂ 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 C-C bonds.