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24. Photocontrol of Reversible Amyloid Formation with a Minimal-Design Peptide

Author

Beatrice Paoli, Peter Hamm, Riccardo Pellarin, Paul M. Donaldson, Steven A. Waldauer, Shabir Hassan, Amedeo Caflisch, Rolf Pfister, University of Zurich, and Hamm, Peter

Subjects
10120 Department of Chemistry, Amyloid, Photoisomerization, Ultraviolet Rays, Stereochemistry, Peptide, Sequence (biology), Molecular Dynamics Simulation, 010402 general chemistry, 01 natural sciences, Protein Structure, Secondary, 03 medical and health sciences, Molecular dynamics, chemistry.chemical_compound, Isomerism, 540 Chemistry, 10019 Department of Biochemistry, Materials Chemistry, Ultraviolet light, Physical and Theoretical Chemistry, 2505 Materials Chemistry, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, 2508 Surfaces, Coatings and Films, Hydrogen Bonding, Fluorescence, 0104 chemical sciences, Surfaces, Coatings and Films, Cross-Linking Reagents, chemistry, Azobenzene, 570 Life sciences, biology, Peptides, 1606 Physical and Theoretical Chemistry, Azo Compounds
Abstract

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.

Published
2012

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