Non-equilibrium modeling of directed flux through biomolecular condensates

Cellular biomolecular condensates function far from equilibrium, sustained by continuous influx and efflux of molecular components. Notable examples include the nucleolus, nuclear pore complex, P-bodies, and stress granules, in which regulated molecular transport is essential for their function. Experimental characterization of molecular flux remains challenging due to limitations in spatiotemporal resolution, making computational approaches a powerful alternative for systematic investigation. Here, we present a computational approach (TRACE) to model molecular transport through biomolecular condensates under non-equilibrium steady-state conditions at near-atomistic resolution. Using TRACE, we systematically probe physicochemical factors that govern molecular flux through condensates. We find that protein sequence composition and patterning determine the internal structure of the condensates, which strongly influences molecular transport efficiency. Our work also suggests that molecular flux through condensates exhibits reptation dynamics. Moreover, interactions between fluxing molecules and condensates play a critical role in regulating transport. In particular, associative interactions enable a handoff mechanism, in which successive transient interactions facilitate directed transport through condensates. Together, these results help advance our understanding on how molecular flux is regulated in biomolecular condensates and provide a basis for rationally tuning condensate-mediated molecular flux, with potential applications in therapeutics and active soft material design.