Exploring Helical Folding in Oligomers of Cyclopentane-Based ϵ-Amino Acids: A Computational Study

The conformational preferences of oligopeptides of an ϵ-amino acid (2-((1R,3S)-3-(aminomethyl)cyclopentyl)acetic acid, Amc₅ a) with a cyclopentane substituent in the C^β -C^γ -C^δ sequence of the backbone were investigated using DFT methods in chloroform and water. The most preferred conformation of Amc₅ a oligomers (dimer to hexamer) was the H₁₆  helical structure both in chloroform and water. Four residues were found to be sufficient to induce a substantial H₁₆ helix population in solution. The Amc₅ a hexamer adopted a stable left-handed (M)-2.3₁₆ helical conformation with a rise of 4.8 Å per turn. The hexamer of Ampa (an analogue of Amc₅ a with replacing cyclopentane by pyrrolidine) adopted the right-handed mixed (P)-2.9_18/16 helical conformation in chloroform and the (M)-2.4₁₆ helical conformation in water. Therefore, hexamers of ϵ-amino acid residues exhibited different preferences of helical structures depending on the substituents in peptide backbone and the solvent polarity as well as the chain length.