Charged mutations in the FUS low-complexity domain modulate condensate ageing kinetics

The assembly of biomolecular condensates is tightly regulated by the intracellular environment. Disruptions in the balance between condensate formation and dissolution--such as irreversible aggregation of low-complexity aromatic-rich kinked segments (LARKS)--have been implicated in multiple neuropathologies. Here, we employ non-equilibrium, residue-resolution coarse-grained simulations to investigate how specific mutations in FUS, an RNA-binding protein associated with amyotrophic lateral sclerosis and frontotemporal dementia, modulate its phase separation propensity and transition into insoluble aggregates. Our simulations reveal that mutations increasing the content of negatively charged amino acids in the low-complexity domain slow down inter-protein {beta}-sheet accumulation, while preserving the phase diagram and viscoelastic properties of the wild-type sequence. Conversely, mutations increasing the arginine content accelerate disorder-to-order LARKS transitions, driving rapid formation of amorphous kinetically trapped aggregates. Our computational approach thus provides molecular-level insights into how specific amino acid mutations and associated intermolecular interactions control the ageing kinetics of protein condensates, promoting aberrant solid-like phases.