The (i, i + 4) Phe-His interaction studied in an alanine-based alpha-helix.

Two models have been considered for the helix-stabilizing Phe-His+ interaction in C-peptide: (1) the H-bond model in which His+ acts as an H-bond donor and the aromatic ring of Phe acts as an acceptor, and (2) a helix dipole model, in which Phe constrains His so that there is a stronger interaction between His+ and the helix dipole. To decide between these models, we compared the effect on helix stability of the Phe-His interaction near the middle versus close to the C terminus of an alanine-based peptide. The nature of the interaction is the same at either position, in agreement with the H-bond model. The results show further that a weak helix-stabilizing Phe-His interaction can be detected when His is uncharged. Replacement of Phe by the saturated analog Cha (beta-cyclohexylalanine) gives no interaction, as predicted by the H-bond model.