Cation-π interaction in model α-helical peptides

Cation-π interactions are increasingly recognized as important in chemistry and biology. Here we investigate the cation--π interaction by determining its effect on the helicity of model peptides using a combination of CD and NMR spectroscopy. The data show that a single Trp/Arg interaction on the surface of a peptide can make a significant net favorable free energy contribution to helix stability if the two residues are positioned with appropriate spacing and orientation. The solvent-exposed Trp→Arg (i, i + 4) interaction in helices can contribute -0.4 kcal/mol to the helix stability, while no free energy gain is detected if the two residues have the reversed orientation, Arg→Trp (i, i + 4). The derived free energy is consistent with other experimental results studied in proteins or model peptides on cation-π interactions. However in the same system the postulated Phe/Arg (i, i + 4) cation-π interaction provides no net free energy to helix stability. Thus the Trp→Arg interaction is stronger than Phe→Arg. The cation-π interactions are not sensitive to the screening effect by adding neutral salt as indicated by salt titration. Our results are in qualitative agreement with theoretical calculations emphasizing that cation-π interactions can contribute significantly to protein stability with the order Trp > Phe. However, our and other experimental values are significantly smaller than estimates from theoretical calculations.