A thermodynamic description of biomolecular condensates

Biomolecular condensates are intracellular membrane-less accumulations of proteins and other molecules at a higher concentration than the rest of the cell. The recent characterization of condensates as liquid-like assemblies has stimulated profound interest in how physical properties of condensates impact molecular biology. Intriguingly, condensates have been shown to be essential to multiple different cellular processes and underlying aspects of various diseases. Yet, the physics of condensate formation remains unsolved. Here, it is shown that intrinsically disordered protein-protein binding alone provides energetically favorable thermodynamics for condensate formation. The reduction in free energy achieved through increased binding at high condensate concentrations can overcome the entropic cost of de-mixing. Formation of condensates is governed by the ratio of total protein concentration to binding affinity ([protein]total/Kd). Yet, stable condensation is only possible through interactions with rapid binding dynamics. The model prediction and experimental observation that condensates are no longer formed at high [protein]total/Kd ratios redefines our understanding of condensate physics and impact on cellular biology.