Influence of substituents on conformational preferences of helix foldamers of γ-dipeptides

ABSTRACT Conformational preferences of 9‐ and 14‐helix foldamers have been studied for γ‐dipeptides of 2‐aminocyclohexylacetic acid (γAc6a) residues such as Ac‐(γAc6a)2‐NHMe (1), Ac‐(Cα‐Et‐γAc6a)2‐NHMe (2), Ac‐(γAc6a)2‐NHBn (3), and Ac‐(Cα‐Et‐γAc6a)2‐NHBn (4) at the M06‐2X/cc‐pVTZ//M06‐2X/6‐31 + G(d) level of theory to explore the influence of substituents on their conformational preferences. In the gas phase, the 9‐helix foldamer H9 and 14‐helix foldamer H14‐z are found to be most preferred for dipeptides 2 and 4, respectively, as for dipeptides 1 and 3, which indicates no remarkable influence of the Cα‐ethyl substitution on conformational preferences. The benzyl substitution at the C‐terminal end lead H14‐z to be the most preferred conformer for dipeptides 3 and 4, whereas it is H9 for dipeptides 1 and 2, which can be ascribed to the favored CH···π interactions between the cyclohexyl group of the first residue and the C‐terminal benzyl group. There are only marginal changes in backbone structures and the distances and angles of H‐bonds for all local minima by Cα‐ethyl and/or benzyl substitutions. Although vibrational frequencies and intensities of the dipeptide 4 calculated at both M06‐2X/6‐31 + G(d) and M05‐2X/6‐31 + G(d) levels of theory are consistent with observed results in the gas phase, H14‐z is predicted to be most preferred by ΔG only at the former level of theory. Hydration did not bring the significant changes in backbone structures of helix foldamers for both dipeptide 1 and 4. It is expected that the different substitutions at the C‐terminal end lead to the different helix foldamers, which may increase the resistance of helical structures to proteolysis and provide the more surface to the helical structures suitable for molecular recognition. © 2014 Wiley Periodicals, Inc. Biopolymers 101: 1077–1087, 2014.