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 Cβ -Cγ -Cδ 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)-2.918/16 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.