Multi-length scale structural investigation of lysozyme self-assembly

Reactive amyloid oligomers are responsible for cytotoxicity in amyloid pathologies and because of their unstable nature characterizing their behavior is a challenge. The physics governing the self-assembly of proteins in crowded conditions is extremely complex and its comprehension, despite its paramount relevance to understanding molecular mechanisms inside cells and optimizing pharmaceutical processes, remains inconclusive. Here, we focus on the amyloid oligomerization process in self-crowded lysozyme aqueous solutions in acidic conditions. We reveal that the amyloid oligomers form at high protein concentration and low pH. Through multi-length scale spectroscopic investigations, we find that amyloid oligomers can further interconnect with each other by weak and non-specific interactions forming an extended network that leads to the percolation of the whole system. Our multi-length scale structural analysis follows the thermal history of amyloid oligomers from different perspectives and highlights the impact of hierarchical self-assembly of biological macromolecules on functional properties.