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Photocontrol of reversible amyloid formation with a minimal-design peptide

S.A. Waldauer; S. Hassan; B. Paoli; P.M. Donaldson; R. Pfister; P. Hamm; A. Caflisch; R. Pellarin

Journal: J. Phys. Chem. B
Year: 2012
Volume: 116
Issue: 30
Pages: 8961-8973
DOI: 10.1021/jp305311z
Type of Publication: Journal Article

Amyloid; Azo Compounds; Cross-Linking Reagents; Hydrogen Bonding; Isomerism; Molecular Dynamics Simulation; Peptides; Protein Structure, Secondary; Ultraviolet Rays


Amyloid aggregates are highly ordered fibrillar assemblies of polypeptides involved in a number of neurodegenerative diseases. Very little is known on the pathways of self-assembly of peptides into the final amyloid fibrils, which is due in part to the difficulty of triggering the aggregation process in a controlled manner. Here we present the design and validation of a cross-linked hexapeptide that reversibly aggregates and dissociates under ultraviolet light irradiation control. First molecular dynamics simulations were carried out to identify, among hundreds of possible sequences, those with the highest propensity to form ordered (β-sheet) oligomers in the trans state of the azobenzene cross-linker, and at the same time with the highest solubility in the cis state. In the simulations, the peptides were observed to spontaneously form ordered oligomers with cross-β contacts when the cross-linker was in the trans state, whereas in the cis state they self-assemble into amorphous aggregates. For the most promising sequence emerging from the simulations (Ac-Cys-His-Gly-Gln-Cys-Lys-NH2 cross-linked at the two cysteine residues), the photoisomerization of the azobenzene group was shown to induce reversible aggregation by time-resolved light scattering and fluorescence measurements. The amyloid-like fibrillar topology was confirmed by electron microscopy. Potential applications of minimally designed peptides with photoswitchable amyloidogenic propensity are briefly discussed.