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

The conformational preferences of oligopeptides of an epsilon-amino acid (2-((1R,3S)-3-(aminomethyl)cyclopentypacetic acid, Amc(5)a) with a cyclopentane substituent in the C-beta-C-gamma-C-delta sequence of the backbone were investigated using DFT methods in chloroform and water. The most preferred conformation of Amc(5)a oligomers (dimer to hexamer) was the H-16 helical structure both in chloroform and water. Four residues were found to be sufficient to induce a substantial H-16 helix population in solution. The Amc(5)a hexamer adopted a stable left-handed (M)-2.3(16) helical conformation with a rise of 4.8 angstrom per turn. The hexamer of Ampa (an analogue of Amc(5)a with replacing cyclopentane by pyrrolidine) adopted the right-handed mixed (P)-2.9(18/16) helical conformation in chloroform and the (A4)-2.4(16) helical conformation in water. Therefore, hexamers of epsilon-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.