Controlling biomolecular condensates via chemical reactions

Abstract: Biomolecular condensates are small droplets forming spontaneously in biological cells via phase separation. They play a role in many cellular processes, but it is unclear how cells control them. Cellular regulation often relies on post-translational modifications of proteins. For biomolecular condensates, such chemical modifications could alter the molecular interaction of key condensate components. We here test this idea using a theoretical model based on non-equilibrium thermodynamics. In particular, we describe the chemical reactions using transition-state theory, which accounts for the non-ideality of phase separation. We identify that fast control, like in cell signaling, is only possible when external energy input drives the reaction out of equilibrium. If this reaction differs inside and outside the droplet, it is even possible to control droplet sizes. Such an imbalance in the reaction could be created by enzymes localizing to the droplet. Since this situation is typical inside cells, we speculate that our proposed mechanism is used to stabilize multiple droplets with independently controlled size and count. Our model provides a novel and thermodynamically consistent framework for describing droplets subject to non-equilibrium chemical reactions.