Effect of Halogenation on Edge−Face Aromatic Interactions in a β-Hairpin Peptide: Enhanced Affinity with Iodo-Substituents

[reaction: see text] In a model beta-hairpin peptide, we have found that the favorable interaction of cross-strand aromatic rings can be enhanced by up to 1 kcal mol(-1) with halogen substituents. It appears that the polarizability of the halogen atoms accounts for the increase in stability and that there is a direct interaction between the N-terminal phenylalanine and the halogen atom. Thermal denaturation studies indicate that the interaction is enthalpically driven with an associated entropic cost. These findings have relevance to areas of molecular recognition and drug design.