Role of a two-residue spacer in an α,β-didehydrophenylalanine containing hexapeptide: crystal and solution structure of Boc-Val-ΔPhe-Leu-Ala-ΔPhe-Ala-OMe

Abstract

The peptide Boc-Val¹-ΔPhe²-Leu³-Ala⁴-ΔPhe⁵-Ala⁶-OMe has been examined for the structural consequence of placing a two-residue segment between the ΔPhe residues. The peptide is stabilized by four consecutive β-turns. The overall conformation of the molecule is a right-handed 3₁₀-helix, with average (Φ, ψ) values (−67.7°, −22.7°), unwound at the C-terminus. The ¹H NMR results also suggest that the peptide maintains its 3₁₀-helical structure in solution as observed in the crystal state. The crystal structure is stabilized through head-to-tail hydrogen bonds and a repertoire of aromatic interactions laterally directed between adjacent helices, which are antiparallel to each other. The aromatic ring of ΔPhe⁵ forms the hub of multicentred interactions, namely as a donor in aromatic C-H^...π and aromatic C-H^...O-C interactions and as an acceptor in a CH₃^...π interaction. The present structure uniquely illustrates the unusual capability of a ΔPhe ring to host such concerted interactions and suggests its exploitation in introducing long-range interactions in the folding of supersecondary structures.