Helix foldamers of γ-peptides based on 2-aminocyclohexylacetic acid: a computational study

Abstract

The conformational preferences of helix foldamers have been studied for oligo-γ-peptides of 2-aminocyclohexylacetic acid (γAc₆a) with a cyclohexyl constraint on the C^β–C^γ bond using density functional methods. For the di-γAc₆a peptide with the homochiral (1S,2S) configurations, the right-handed (P) 9-helical structure is found to be the most preferred in the gas phase, whereas the (P) 14-helical structure is favored by ∼0.2 kcal mol⁻¹ over the former in water. As the peptide sequence becomes longer, the (P)-2.5₁₄-helices are the most preferred for tetra- to octa-γAc₆a peptides both in the gas phase and in water, which is due to the favored conformational energies. The calculated mean backbone torsion angles and helical parameters of the 14-helix foldamers of oligo-γAc₆a peptides are consistent with those of the X-ray structures of C^α-ethyl-γAc₆a peptides. Although the 14-helix foldamers of γAc₆a and 2-(aminomethyl)cyclohexanecarboxylic acid (γAmc₆) oligopeptides have similar mean backbone torsion angles and helical parameters, there are some differences in structure and/or helix handedness for other helix foldamers, which can be ascribed to the different substitutions of the cyclohexyl constraint on C^β–C^γ or C^α–C^β bonds. Therefore, the conformational preferences of the oligo-γAc₆a peptides obtained here are expected to provide useful information for structure-based designs of biologically active γ-peptides with specific functions.