A Photoswitchable Tryptophan Zipper – (Un)folding Fibrils in Seconds

Peptides and proteins, that have the tendency to form aggregates, are often discussed in the context of Alz-heimer’s, Huntington’s, or Parkinson’s disease. However, studying aggregation processes is inherently challenging due to the due to the diversity of aggregate size and geometry and the lack of control over the aggregation process in space and time. Here, we present a small, synthetic peptide, for which aggregation can be controlled reversibly with light within seconds. Specifically, by incorporating photoswitchable unnatural amino acids into the sequence of a tryptophan zipper, we could cre-ate the A3Tz5 peptide, which can switch its secondary structure between a β-hairpin and a β-sheet-like structure through photoisomerization. We provide a detailed insight into the molecular interactions involved in this process by combining var-ious spectroscopies and microscopy techniques. With A3Tz5 in hand, we overcame the limitation of spatiotemporal control in aggregation processes opening the door towards disease relevant studies.