Amyloid aggregates are highly ordered fibrillar assembliesof polypeptidesinvolved in a number of neurodegenerative diseases. Very little isknown on the pathways of self-assembly of peptides into the finalamyloid fibrils, which is due in part to the difficulty of triggeringthe aggregation process in a controlled manner. Here we present thedesign and validation of a cross-linked hexapeptide that reversiblyaggregates 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 propensityto form ordered (β-sheet) oligomers in the trans state of theazobenzene cross-linker, and at the same time with the highest solubilityin the cis state. In the simulations, the peptides were observed tospontaneously form ordered oligomers with cross-β contacts whenthe cross-linker was in the trans state, whereas in the cis statethey self-assemble into amorphous aggregates. For the most promisingsequence emerging from the simulations (Ac-Cys-His-Gly-Gln-Cys-Lys-NH2cross-linked at the two cysteine residues), the photoisomerizationof the azobenzene group was shown to induce reversible aggregationby time-resolved light scattering and fluorescence measurements. Theamyloid-like fibrillar topology was confirmed by electron microscopy.Potential applications of minimally designed peptides with photoswitchableamyloidogenic propensity are briefly discussed. [ABSTRACT FROM AUTHOR]