Extreme dynamics in a biomolecular condensate

Abstract

Two highly charged disordered human proteins phase-separate into viscous complex coacervates while retaining their rapid conformational dynamics through pico- to nanosecond exchange of short-lived side-chain interactions. Proteins and nucleic acids can phase-separate in the cell to form concentrated biomolecular condensates^ 1 – 4 . The functions of condensates span many length scales: they modulate interactions and chemical reactions at the molecular scale^ 5 , organize biochemical processes at the mesoscale^ 6 and compartmentalize cells^ 4 . Understanding the underlying mechanisms of these processes will require detailed knowledge of the rich dynamics across these scales^ 7 . The mesoscopic dynamics of biomolecular condensates have been extensively characterized^ 8 , but their behaviour at the molecular scale has remained more elusive. Here, as an example of biomolecular phase separation, we study complex coacervates of two highly and oppositely charged disordered human proteins^ 9 . Their dense phase is 1,000 times more concentrated than the dilute phase, and the resulting percolated interaction network^ 10 leads to a bulk viscosity 300 times greater than that of water. However, single-molecule spectroscopy optimized for measurements within individual droplets reveals that at the molecular scale, the disordered proteins remain exceedingly dynamic, with their chain configurations interconverting on submicrosecond timescales. Massive all-atom molecular dynamics simulations reproduce the experimental observations and explain this apparent discrepancy: the underlying interactions between individual charged side chains are short-lived and exchange on a pico- to nanosecond timescale. Our results indicate that, despite the high macroscopic viscosity of phase-separated systems, local biomolecular rearrangements required for efficient reactions at the molecular scale can remain rapid.