Aromatic interactions with naphthylalanine in a β-hairpin peptide

Abstract

Stable peptides have been explored as epitope mimics for protein-protein and protein-nucleic acid interactions; however, presentation of a regular structure is critical. Aromatic interactions are ubiquitous and are competent at stabilizing a β-hairpin fold. The greatest stabilization has been reported from pairs of tryptophan side chains. Naphthylalanine residues are often used as tryptophan replacements, but it is not clear if 1-naphthylalanine or 2-naphthylalanine is adequate at replicating the geometry and stability observed with tryptophan aromatic interactions. Herein, a 12-residue peptide has been constructed with laterally disposed aromatic amino acids. A direct comparison is made between tryptophan and other bicyclic, unnatural amino acids. Significant stabilization is gained from all bicyclic amino acids; however, geometric analysis shows that only 1-naphthylalanine adopts a similar edge to face geometry as tryptophan, whereas the 2-naphthylalanine appears most similar to a substituted phenylalanine. © 2013 European Peptide Society and John Wiley & Sons, Ltd.