De Novo Design of α,β-Didehydrophenylalanine Containing Peptides: From Models to Applications

The de novo design of peptides and proteins has emerged as an approach for investigating protein structures and function. The success relies heavily on the ability to design relatively short peptides that can adopt stable secondary structures. To this end, substitution with alpha,beta-dehydroamino acids, especially alpha,beta-didehydrophenylalanine (Delta Phe or Delta F) has blossomed in manifold directions, providing a rich diversity of well-defined structural motifs. Introduction of alpha,beta-didehydrophenylalanine induces beta-bends in small and 3(10)-helices-in longer peptide sequences. Most favorable conformation of Delta F residues are (phi,psi)similar to(60 degrees, 30), (-60 degrees, -30 degrees), (-60 degrees, 150 degrees), and (60 degrees, -150 degrees). These features have been exploited in designing helix-turn-helix, helical bundle arrangements, and glycine zipper type super secondary structural motifs. The unusual capability of alpha,beta-didehydrophenylalanine ring to form a variety of multicentered interactions (N-H center dot center dot center dot O, C-H center dot center dot center dot pi, C-H center dot center dot center dot pi, and N-H center dot center dot center dot pi) suggests its possible exploitation for future de novo design of supramolecular structures. This work has now been extended to the de novo design of peptides with antibiotic, antifibrillization activity, etc. More recently, self-assembling properties of small dehydropeptides have beenexplored. This review focuses primarily on the structural and functional behavior of alpha,beta-didehychyphenylalanine containing peptides. (C) 2010 Wiley Periodicals, Inc. Biopolymers 95: 161-173, 2011.