Tryptophan residues: Scarce in proteins but strong stabilizers of β‐hairpin peptides

Tryptophan plays important roles in protein stability and recognition despite its scarcity in proteins. Except as fluorescent groups, they have been used rarely in peptide design. Nevertheless, Trp residues were crucial for the stability of some designed minimal proteins. In 2000, Trp–Trp pairs were shown to contribute more than any other hydrophobic interaction to the stability of β‐hairpin peptides. Since then, Trp–Trp pairs have emerged as a paradigm for the design of stable β‐hairpins, such as the Trpzip peptides. Here, we analyze the nature of the stabilizing capacity of Trp–Trp pairs by reviewing the β‐hairpin peptides containing Trp–Trp pairs described up to now, the spectroscopic features and geometry of the Trp–Trp pairs, and their use as binding sites in β‐hairpin peptides. To complete the overview, we briefly go through the other relevant β‐hairpin stabilizing Trp–non‐Trp interactions and illustrate the use of Trp in the design of short peptides adopting α‐helical and mixed α/β motifs. This review is of interest in the field of rational design of proteins, peptides, peptidomimetics, and biomaterials. © 2010 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 94: 779–790, 2010. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com