A Photochromic Azobenzene Peptidomimetic of a β-Turn Model Peptide Structure as a Conformational Switch

Abstract

The insertion of azobenzene moiety in complex molecular protein or peptide systems can lead to molecular switches to be used to determine kinetics of folding/unfolding properties of secondary structures, such as α-helix, β-turn, or β-hairpin. In fact, in azobenzene, absorption of light induces a reversible trans ↔ cis isomerization, which in turns generates a strain or a structure relaxation in the chain that causes peptide folding/unfolding. In particular azobenzene may permit reversible conformational control of hairpin formation. In the present work a synthetic photochromic azobenzene amino acid derivative was incorporated as a turn element to modify the synthetic peptide [Pro 7 ,Asn 8 ,Thr 10 ]CSF114 previously designed to fold as a type I β-turn structure in biomimetic HFA/water solution. In particular, the P-N-H fragment at positions 7–9, involved in a β-hairpin, was replaced by an azobenzene amino acid derivative (synthesized ad hoc ) to investigate if the electronic properties of the novel peptidomimetic analog could induce variations in the isomerization process. The absorption spectra of the azopeptidomimetic analog of the type I β-turn structure and of the azobenzene amino acid as control were measured as a function of the irradiation time exciting into the respective first ππ * and nπ * transition bands. Isomerization of the azopeptidomimetic results strongly favored by exciting into the ππ * transition. Moreover, conformational changes induced by the cis ↔ trans azopeptidomimetic switch were investigated by NMR in different solvents.

Hydrazone Photoswitches for Structural Modulation of Short Peptides

“…On the other hand, Pep2 ‐ E shows a ROE correlation between the hydrazone NH and ortho proton of the upper phenyl ring [65] . ROESY experiments of Pep2 corroborate distinct configurational isomers of the hydrazone unit, demonstrating that E / Z isomerization of the hydrazone can fold/unfold the peptide backbone as a photoswitchable hinge [50] . No ROE correlation between the peptide chains is observed, which is presumably attributed to the highly floppy backbone conformation.…”

“…[65] ROESY experiments of Pep2 corroborate distinct configurational isomers of the hydrazone unit, demonstrating Chemistry-A European Journal that E/Z isomerization of the hydrazone can fold/unfold the peptide backbone as a photoswitchable hinge. [50] No ROE correlation between the peptide chains is observed, which is presumably attributed to the highly floppy backbone conformation. Although the structural modulation of Pep2 was successful, its repeated photoswitching cycles led to gradual appearance of new species in 1 H NMR (Figure S93, Supporting Information), which is ascribed to the aforementioned photoswitching fatigue of the hydrazone unit.…”

“…Peptides are oligomers of amino acids whose secondary structures and activities can be altered drastically by a photoswitching process. [40][41][42][43][44][45] To this end, various photoswitches such as azobenzenes, [46][47][48][49][50][51] stilbenes, [52] diarylethenes, [53,54] fumaramides, [55,56] and overcrowded alkenes [57] have been tethered to the side chains or incorporated into the peptide backbones, and their photoisomerizations facilitated regulation of cell membrane permeability, [58] enzymatic activity, [59,60] and receptor binding. [61,62] Thus we envisioned that hydrazone photoswitches would constitute a novel class of structural and functional modulators of bioactive peptides if the aforemen-tioned superior switching properties can be successfully introduced.…”

Push/Pull Effect as Driving Force for Different Optical Responses of Azobenzene in a Biological Environment

“…The photoswitching of azobenzene based micelles has been found to be highly reversible but can be suppressed in aggregates precipitated from the solution . Azobenzene derivatives have been used as surfactants bound to DNA to induce and control conformational changes , to get insight into a stabilization of RNA and DNA hairpins. − Böckmann et al developed an atomistic force field for a compound which has been used to achieve photoisomerization driven peptide folding. − In literature, engineered biological pores responsive to external stimuli have been fruitfully used for various biotechnological applications, and azobenzene as a controlled artificial on/off switch has been found to provide a temporal control of designed nanodevices. − …”

A refined photo‐switchable cyclic peptide scaffold for use in β‐turn activation

“…[7][8][9][10] These molecules undergo cis-trans isomerization of the azobenzene in a controlled fashion via ultraviolet (UV) light. The azobenzene moiety has been used for α-helix stabilization, [11][12][13][14][15] β-turn formation, [16][17][18] β-sheet formation, [19][20][21] protein binding and activation, [22][23][24] cellmediated binding, [25][26][27] and within DNA. [28][29][30][31][32] More specifically, an azobenzene-containing amino acid, (4-aminomethyl)phenylazobenzoic acid (azo), and its derivatives can be used to promote light mediated conformational switching that can selectively initiate a range of chemical responses.…”