Molecular origins of viscoelasticity in biomolecular condensates.

Biomolecular condensates are membraneless organelles that compartmentalize functions in living cells. Formed by the phase separation of biomolecules, condensates possess a wide range of mechanical responses. However, how condensate viscoelastic response is encoded in the chemistries of their constituents-such as intrinsically disordered proteins (IDPs)-is not well understood. Here, we employ molecular dynamics simulations to connect measurable condensate viscoelasticity to the architectural heterogeneity and dynamic reconfigurability of associative networks formed by IDPs. Using a residue-resolution coarse-grained model, we characterize biologically relevant and synthetic condensates, demonstrating that the temperature sensitivity of elasticity is sequence-dependent and modeled by exponential scaling laws. We interrogate condensate mesh heterogeneity via entanglement spacing, finding that entropy-driven structural heterogeneity and reduced IDP hydrophobicity favor condensate elasticity. Furthermore, we construct graph-theoretical representations of condensates and find that interaction network topologies with an abundance of redundant node pathways translate to more load-bearing paths for mechanical stress storage. Strikingly, we discover that elastic coupling of IDPs within condensates emerges when single-molecule shape memory timescales approach mesh reconfiguration timescales. This interplay of timescales for molecular and microstructural processes, which we introduce as the condensate Deborah number, dictates how restoring elastic forces propagate and are stored across IDP networks, linking condensate microstructure dynamics directly to mechanical responses. Taken together, our work provides a conceptual framework of how condensates act as stress-responsive biomaterials, helping illuminate how cells exploit condensate mechanics to sense and regulate their internal environment and opening avenues for the design of condensates with programmable viscoelastic properties.