Photocontrol of reversible amyloid formation with a minimal-design peptide.
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-NH(2) 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.
Institute of Physical Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Steven A
SA
Waldauer
Shabir
S
Hassan
Beatrice
B
Paoli
Paul M
PM
Donaldson
Rolf
R
Pfister
Peter
P
Hamm
Amedeo
A
Caflisch
Riccardo
R
Pellarin
D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism; D001391:Azo Compounds / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D006860:Hydrogen Bonding; D007536:Isomerism; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D014466:Ultraviolet Rays
D000682:Amyloid; D001391:Azo Compounds; D003432:Cross-Linking Reagents; D010455:Peptides; C009850:azobenzene