Predicting mesoscopic properties of condensates from nanoscale dynamics

Biomolecular condensates form by phase separation of biological polymers. The cellular functions of such membraneless organelles are closely linked to their physical properties across length- and timescales: from the nanoscale dynamics of individual molecules, to the microscale translational diffusion within condensates, and to their mesoscale viscoelasticity. However, the quantitative relationships between these characteristics have remained unclear. We address this question by combining single-molecule fluorescence, nanosecond correlation spectroscopy, microrheology, and large-scale molecular dynamics simulations, which we have applied to different condensates formed by complex coacervation of highly charged disordered proteins spanning about two orders of magnitude in molecular dynamics, diffusivity, and viscosity. We find that the nanoscale chain dynamics of proteins in the dense phases occurs on timescales from ~100 ns to ~10 μs. Remarkably, the chain dynamics can be related quantitatively to both translational diffusion and mesoscale condensate viscosity by analytical relations from polymer theory. Slight improvements in force fields now open the possibility of predicting mesoscopic properties of condensates from MD simulations.