A Photocontrolled β-Hairpin Peptide

β‐Hairpins constitute the smallest β‐type structures in peptides and proteins. The development of highly stable, yet monomeric β‐hairpins based on the tryptophan zipper motif was therefore a remarkable success [A. G. Cochran, N. J. Skelton, M. A. Starovasnik, Proc. Natl. Acad. Sci USA 2001, 98, 5578–5583]. We have been able to design, synthesize and characterize a hairpin based on this motif which incorporates an azobenzene‐based photoswitch, that allows for time‐resolved folding studies of β‐structures with unprecedented time resolution. At room temperature the trans‐azo isomer exhibits a mostly disordered structure; however, light‐induced isomerization to the cis‐azo form leads to a predominantly extended and parallel conformation of the two peptide parts, which are linked by the novel photoswitch, [3‐(3‐aminomethyl)phenylazo]phenylacetic acid (AMPP). While in the original sequence the dipeptide Asn‐Gly forms a type I′ β‐turn which connects the two strands of the hairpin, this role is adopted by the AMPP chromophore in our photoresponsive β‐hairpin that can apparently act as a β I′‐turn mimetic. The β‐hairpin structure was determined and confirmed by NMR spectroscopy, but the folding process can be monitored by pronounced changes in the CD, IR and fluorescence spectra. Finally, incorporation of the structurally and functionally important β‐hairpin motif into proteins by chemical ligation might allow for the photocontrol of protein structures and/or functions. Lights on! A hairpin model, which incorporated the βI′ turn mimetic [3‐(3‐aminomethyl)‐phenylazo]phenylacetic acid inbetween two peptide strands, resulted in a β‐hairpin model in which the folding/unfolding of this structural motif is controlled by the isomeric state of the azobenzene chromophore. Pronounced changes in the CD, IR, and fluorescence spectra enable time‐resolved folding studies by ultra‐fast spectroscopy upon photoisomerization.