Location and Concentration of Aromatic‐Rich Segments Dictates the Percolating Inter‐Molecular Network and Viscoelastic Properties of Ageing Condensates

Abstract

AbstractMaturation of functional liquid‐like biomolecular condensates into solid‐like aggregates has been linked to the onset of several neurodegenerative disorders. Low‐complexity aromatic‐rich kinked segments (LARKS) contained in numerous RNA‐binding proteins can promote aggregation by forming inter‐protein β‐sheet fibrils that accumulate over time and ultimately drive the liquid‐to‐solid transition of the condensates. Here, atomistic molecular dynamics simulations are combined with sequence‐dependent coarse‐grained models of various resolutions to investigate the role of LARKS abundance and position within the amino acid sequence in the maturation of condensates. Remarkably, proteins with tail‐located LARKS display much higher viscosity over time than those in which the LARKS are placed toward the center. Yet, at very long timescales, proteins with a single LARKS—independently of its location—can still relax and form high viscous liquid condensates. However, phase‐separated condensates of proteins containing two or more LARKS become kinetically trapped due to the formation of percolated β‐sheet networks that display gel‐like behavior. Furthermore, as a work case example, they demonstrate how shifting the location of the LARKS‐containing low‐complexity domain of FUS protein toward its center effectively precludes the accumulation of β‐sheet fibrils in FUS‐RNA condensates, maintaining functional liquid‐like behavior without ageing.