Helix preferences of cyclopentane-containing β/γ-hybrid peptides

Abstract

The helix preferences of cyclopentane-containing β/γ-hybrid oligomers, consisting of alternating βAc₅a (2-aminocyclopentanecarboxylic acid) and γ(Et)Ac₅a [2-(2-aminocyclopentyl)butanoic acid] residues with homochiral S-configurations, were investigated through conformational searches and density functional theory calculations in chloroform. The β/γ-hybrid dimer exhibited a distinct inclination toward a ribbon-like structure characterized by alternating C₈ and C₉ H-bonds. However, for β/γ-hybrid oligomers longer than tetramer, a preference for a right-handed (P)-2.4₁₃-helical structure emerged. The robust stabilities observed for the H₁₃ helical structures in chloroform were attributed to the favored solvation free energies, which increased with the length of the peptide sequence. Calculations revealed that the mean backbone torsion angles of the H₁₃ helix foldamer in the β/γ-hybrid pentamer closely resembled those observed in X-ray structures of the pentamer consisting of βAc₅a and a γ-residue with a cyclohexane substituent. The introduction of cyclopentane substitutions led to distinct conformational preferences and/or handedness of helix foldamers compared to those of the unsubstituted β/γ-hybrid oligomers. Notably, a pyrrolidine-substituted analog of the H₁₃ helical structure for the β/γ-hybrid pentamer, with adjacent amine diads substituted in close proximity, appears to be a promising organic catalyst for organic reactions such as the crossed aldol condensation and the cyclodimerization of dialdehyde in nonpolar solvents, as previously elucidated.