Fibrils emerging from droplets: Molecular guiding principles behind phase transitions of short peptide-based condensates

17 October 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Biochemical reactions occurring in highly crowded cellular environments require different means of control to ensure productivity and specificity. Compartmentalization of reagents by liquid-liquid phase separation is one of these means. However, extremely high local protein concentrations of up to 400 mg/ml can result in pathological aggregation into fibrillar amyloid structures, a phenomenon that has been linked to various neurodegenerative diseases. Despite its relevance, the process of liquid-to-solid transition inside condensates is still not well understood at the molecular level. In this work, we use small peptide derivatives that can undergo both liquid-liquid and subsequent liquid-to-solid phase transition as model systems to study both processes at the molecular level. Using solid-state nuclear magnetic resonance (NMR) and transmission electron microscopy, we compare the structure of condensed states of leucine, tryptophan and phenylalanine containing derivatives, distinguishing between liquid-like condensates, amorphous aggregates and fibrils, respectively. A structural model for the fibrils formed by the phenylalanine derivative was obtained by a structure calculation based on NMR distance restraints. Our results show that the fibrils are stabilised by hydrogen bonds and side-chain π-π interactions, which are likely much less pronounced or absent in the liquid and amorphous state. Such noncovalent interactions are equally important for the liquid-to-solid phase transition of proteins, particularly those related to neurodegenerative diseases and our results suggest that aged condensates of these proteins may have partial amyloid-like characteristics.


noncovalent interactions
phase transitions
solid-state NMR
π-π interaction

Supplementary materials

Supplementary Material
Figures, tables and experimental details supplementing the findings described in the main text.


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