The de novo design of peptides and proteins has emerged as an approach for investigating protein structure 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 α,β‐dehydroamino acids, especially α,β‐didehydrophenylalanine (ΔPhe or ΔF) has blossomed in manifold directions, providing a rich diversity of well‐defined structural motifs. Introduction of α,β‐didehydrophenylalanine induces β‐bends in small and 310‐helices in longer peptide sequences. Most favorable conformation of ΔF residues are (ϕ,ψ) ∼(60°, 30°), (−60°, −30°), (−60°, 150°), and (60°, −150°). 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 α,β‐didehydrophenylalanine ring to form a variety of multicentered interactions (N‐H…O, C‐H…O, C‐H…π, and N‐H…π) 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 been explored. This review focuses primarily on the structural and functional behavior of α,β‐didehydrophenylalanine containing peptides. © 2010 Wiley Periodicals, Inc. Biopolymers 95: 161–173, 2011.

Inhibition of human islet amyloid polypeptide (hIAPP) fibrillisation by peptides incorporating a helicogenic amino acid, dehydrophenylalanine: implications for Type-2 diabetes.

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De novo designed peptide based super secondary structures are expected to provide scaffolds for the incorporation of functional sites as in proteins. Self-association of peptide helices of similar screw sense, mediated by weak interactions, has been probed by the crystal structure determination of two closely related peptides: Ac-Gly1-Ala2-Delta Phe3-Leu4-Val5-DeltaPhe6-Leu7-Val8-DeltaPhe9-Ala10-Gly11-NH2 (I) and Ac-Gly1-Ala2-DeltaPhe3-Leu4-Ala5-DeltaPhe6-Leu7-Ala8-DeltaPhe9-Ala10-Gly11-NH2 (II). The crystal structures determined to atomic resolution and refined to R factors 8.12 and 4.01%, respectively, reveal right-handed 3(10)-helical conformations for both peptides. CD has also revealed the preferential formation of right-handed 3(10)-helical conformations for both molecules. Our aim was to critically analyze the packing of the helices in the solid state with a view to elicit clues for the design of super secondary structural motifs such as two, three, and four helical bundles based on helix-helix interactions. An important finding is that a packing motif could be identified common to both the structures, in which a given peptide helix is surrounded by six other helices reminiscent of transmembrane seven helical bundles. The outer helices are oriented either parallel or antiparallel to the central helix. The helices interact laterally through a combination of N--H...O, C--H...O, and C--H...pi hydrogen bonds. Layers of interacting leucine residues are seen in both peptide crystal structures. The packing of the peptide helices in the solid state appears to provide valuable leads for the design of super secondary structural modules such as two, three, or four helix bundles by connecting adjacent antiparallel helices through suitable linkers such as tetraglycine segments.

Background: The de novo design of peptides and proteins has recently surfaced as an approach for investigating protein structure and function. This approach vitally tests our knowledge of protein folding and function, while also laying the groundwork for the fabrication of proteins with properties not precedented in nature. The success of these studies relies heavily on the ability to design relatively short peptides that can espouse stable secondary structures. To this end, substitution with α, β-dehydroamino acids, especially α, β-dehydrophenylalanine (∆Phe) comes in use for spawning well-defined structural motifs. Introduction of ∆Phe induces β-bends in small and 3 10 -helices in longer peptide sequences.