Peptide design using ω-amino acids: unusual turn structures nucleated by an N-terminal single γ-aminobutyric acid residue in short model peptides

Abstract

Incorporation of ω-amino acids into peptide sequences plays an important role in designing peptides with modified backbone conformation and enhanced stability against proteolysis. The present study establishes the presence of unusual turns involving 12-membered hydrogen bonded rings in terminally blocked tri- and tetrapeptides. X-ray diffraction analysis of single crystals and NMR studies have been used to probe the three-dimensional structures of two terminally protected short peptides, Boc-γ-Abu(1)-Aib(2)-Ala(3)-OMe 1 and Boc-γ-Abu(1)-Aib(2)-Ala(3)-Aib(4)-OMe 2 (γ-Abu = γ-aminobutyric acid), in which conformationally flexible ω-amino acids (γ-Abu) and conformationally restricted α-aminoisobutyric acid (Aib) residues are positioned contiguously. The crystal structures of both peptides 1 and 2 exhibit unusual turns composed of 12-membered hydrogen bonded rings involving C=O from the Boc-group and Ala(3) NH. A type I' β-turn was observed in the structure of peptide 2 adjacent to the unusual turn with a hydrogen bond between γ-Abu(1) C=O and Aib(4) NH. The crystals of peptide 1 are in the space group P2₁, a = 9.3020(10) Å, b = 23.785(2) Å, c = 10.022(3) Å, β = 101.35°(4), Z = 4, R = 5.7%, and R_w = 14.5%. Similarly, the crystals of peptide 2 are in the space group C2, a = 19.0772(6) Å, b = 8.7883(2) Å, c = 16.7758(3) Å, β = 110.7910°(10), Z = 4, R = 6.71%, and R_w = 15.11%. The unusual turn in both peptides 1 and 2 are retained in solution as is evident from NMR studies in CDCl₃. The role of the adjacently located Aib residue to nucleate the 12-membered hydrogen bonded ring is also addressed.