Biomolecular condensate viscoelasticity is dictated by the interplay between single-molecule shape memory and mesh reconfigurability

Abstract

Biomolecular condensates are membraneless organelles that compartmentalize biological functions in living cells. Formed by the phase separation of biomolecules, condensates possess a wide range of mechanical responses. However, how condensate viscoelastic responses are encoded in the chemistries of their constituents--such as intrinsically disordered proteins (IDPs)--are 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 their 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 translates 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 meshwork reconfiguration timescales. Akin to a condensate Deborah number, this interplay of timescales for molecular and microstructural processes 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 material properties. SIGNIFICANCEBiomolecular condensates are soft materials that exhibit diverse viscoelastic responses. We show how microstructure dynamics dictate condensate mechanics by probing the heterogeneity of local structures and how their connectivity and persistence store elastic stress. Strikingly, we discover that the ratio of timescales of single-protein shape memory to that of the underlying network rearrangement is a robust indicator of whether a condensate is dominantly viscous or elastic. This finding makes condensate mechanics predictable from sequence-dependent "Deborah numbers," which are experimentally accessible. Our work therefore provides a tangible framework for understanding condensate stress dissipation mechanisms and opens opportunities for designing condensates with programmable material properties.