β-turn analogues in model αβ-hybrid peptides: Structural characterization of peptides containing β ^2,2Ac ₆c and β ^3,3Ac ₆c residues

The effect of gem-dialkyl substituents on the backbone conformations of β-amino acid residues in peptides has been investigated by using four model peptides: Boc-Xxx-β ^2,2Ac ₆c(1- aminomethylcyclohexanecarboxylic acid)-NHMe (Xxx=Leu (1), Phe (2); Boc=tert-butyloxycarbonyl) and Boc-Xxx-β ^3,3Ac ₆c(1-aminocyclohexaneacetic acid)-NHMe (Xxx=Leu (3), Phe (4)). Tetrasubstituted carbon atoms restrict the ranges of stereochemically allowed conformations about flanking single bonds. The crystal structure of Boc-Leu-β ^2,2Ac ₆c-NHMe (1) established a C ₁₁ hydrogen-bonded turn in the αβ-hybrid sequence. The observed torsion angles (α(φ≈-60°, ψ≈-30°), β(φ≈-90°, θ≈60°, ψ≈-90°)) corresponded to a C ₁₁ helical turn, which was a backbone-expanded analogue of the type III β turn in αα sequences. The crystal structure of the peptide Boc-Phe-β ^3,3Ac ₆c-NHMe (4) established a C ₁₁ hydrogen-bonded turn with distinctly different backbone torsion angles (α(φ≈-60°, ψ≈120°), β(φ≈60°, θ≈60°, ψ≈-60°)), which corresponded to a backbone-expanded analogue of the type II β turn observed in αα sequences. In peptide 4, the two molecules in the asymmetric unit adopted backbone torsion angles of opposite signs. In one of the molecules, the Phe residue adopted an unfavorable backbone conformation, with the energetic penalty being offset by a favorable aromatic interaction between proximal molecules in the crystal. NMR spectroscopy studies provided evidence for the maintenance of folded structures in solution in these αβ-hybrid sequences.