Sequence-specific interactions determine viscoelastic moduli and aging dynamics of protein condensates

Abstract

Abstract Biomolecular condensates that form via phase separation coupled to percolation are complex viscoelastic materials whose properties are thought to influence cellular functions and pathology. Here, we report results from measurements of sequence-encoded and age-dependent material properties of condensates formed by intrinsically disordered prion-like low complexity domains (PLCDs). Nascent PLCD condensates are viscoelastic Maxwell fluids, and their sequence-specific dynamical moduli are governed by the strengths of aromatic sticker-sticker interactions. These measured moduli are reproducible using a generalized Rouse-Zimm model that accounts for the computed inhomogeneous network-like structures of condensates. PLCD condensates can undergo physical aging that leads to dynamical arrest on sequence-specific timescales. However, contrary to being glass-like, the aged PLCD condensates are non-fibrillar, terminally elastic, Kelvin-Voigt solids. These results suggest that terminally viscous fluid states of condensates are metastable, whereas their terminally elastic solid states are globally stable. The timescales of fluid-to-solid transitions can be controlled by mutations to spacers that weaken the metastability of fluids. Taken together, our results suggest that sequence features of naturally occurring PLCDs enhance the metastabilities of terminally viscous condensates. This likely renders the barriers for conversion from fluids to solids to be insurmountable on timescales that are relevant to condensate functions in cells.