Protein structural transitions critically transform the network connectivity and viscoelasticity of RNA-binding protein condensates but RNA can prevent it

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. In this work the authors propose a multiscale computational approach, integrating atomistic and coarse-grained models simulations, to study the thermodynamic and kinetic factors playing a major role in the liquid-to-solid transition of biomolecular condensates. It is revealed how the gradual accumulation of inter-protein β -sheets increases the viscosity of functional liquid-like condensates, transforming them into gel-like pathological aggregates, and it is also shown how high concentrations of RNA can decelerate such transition.