To study these complex processes, RESOLV researcher Prof. Winter and his team have developed a family of chimeric peptides, ACC1–13Kn, combining an amyloid-forming fragment of insulin (ACC1–13) with various lengths of lysine segments. They found that ATP induces certain reactions. The transition of ACC1–13Kn peptides into liquid droplets or fibrils is triggered by ATP through electrostatic interactions. Additionally, there are different behaviours for different length peptides. Regarding shorter peptides, they directly form amyloid fibrils without forming droplets. Longer peptides initially form liquid droplets, which then transform into amyloid fibrils. The process and stability of fibril formation are highly sensitive to the ionic strength of the environment, indicating that electrostatic interactions are crucial in determining the pathway from LLPS to fibrillization. The fibrils formed in this process are sensitive to hydrostatic pressure due to their dense ionic interactions, as demonstrated using infrared spectroscopy. Using atomic force microscopy, researchers observed that fibrils start forming at the interface of the liquid droplets and the surrounding solution, beginning as single bent fibres.

The balance between hydrophobic and electrostatic interactions modulates whether proteins form liquid droplets or fibrils. This balance is influenced by factors like the length of lysine segments, ATP concentration, and salt levels. Similar mechanisms may be at play in proteins associated with diseases, such as those seen in Alzheimer's and Parkinson's. Understanding these pathways can offer new insights into disease progression and potential treatments. While traditionally considered a benign molecule, ATP at physiological concentrations can significantly influence protein aggregation, challenging its earlier reputation.

This study presents a detailed model of how protein dysfunction pathways can be studied and manipulated. The use of chimeric peptides like ACC1–13Kn allows to understand the complex interplay between liquid droplet formation and amyloid fibril creation, offering the potential for better understanding and treatment of protein-related diseases.