Biomolecular condensates, some of which are liquid-like during health, can age over time becoming gel-like pathological systems. One potential source of loss of liquid-like properties during ageing of RNA-binding protein condensates is the progressive formation of inter-protein β-sheets. To bridge microscopic understanding between accumulation of inter-protein β-sheets over time and the modulation of FUS and hnRNPA1 condensate viscoelasticity, we develop a multiscale simulation approach. Our method integrates atomistic simulations with sequence-dependent coarse-grained modelling of condensates that exhibit accumulation of inter-protein β-sheets over time. We reveal that inter-protein β-sheets notably increase condensate viscosity but does not transform the phase diagrams. Strikingly, the network of molecular connections within condensates is drastically altered, culminating in gelation when the network of strong β-sheets fully percolates. However, high concentrations of RNA decelerate the emergence of inter-protein β-sheets. Our study uncovers molecular and kinetic factors explaining how the accumulation of inter-protein β-sheets can trigger liquid-to-solid transitions in condensates, and suggests a potential mechanism to slow such transitions down.

Biomolecular condensates, some of which are liquid-like during health, can age over time becoming gel-like pathological systems. Ageing of RNA-binding protein condensates can emerge from the progressive accumulation of inter-protein β-sheets. To bridge microscopic understanding of such time-dependent transformation with the modulation of FUS and hnRNPA1 condensate viscoelasticity, we develop a multiscale simulation approach. Our method integrates atomistic simulations with sequence-dependent coarse-grained modelling of condensates that age over time due to accumulation of inter-protein β-sheets. We reveal that ageing notably increases condensate viscosity but does not transform the phase diagrams. Strikingly, the network of molecular connections within condensates is drastically altered during ageing and culminates in gelation when the network of strong inter-protein β-sheets fully percolates. High concentrations of RNA decelerate the accumulation of inter-protein β-sheets, abrogating the effects of ageing. Our study uncovers molecular and kinetic factors explaining condensate ageing, and suggests a potential mechanism to slow ageing down.