Dimerization thermodynamics govern biological phase separation

Many intrinsically disordered proteins/regions (IDR) can phase separate into a liquid state (biomolecular condensates) and/or a solid state (aggregates and amyloids). De-mixing in liquid-like phase separation carries an entropic cost that must be balanced by an energetic advantage of condensing. Yet, the mechanism of this energetic advantage remains unclear. Here, it is shown that an increase in dimerization binding interactions through liquid-like condensation can create overall energetic minimums when a system phase separates. Yet, the dimer binding interactions must be rapid explaining why IDRs are so prominent in phase separations. Numerous experimental examples that can only be described through dimer interactions support the dimer model presented here. The transition from condensates to aggregates and amyloids under certain conditions also appears to be driven by dimer abundance. Overall, the dimer model provides a novel theory that solves the thermodynamic mechanism of protein phase separation into biomolecular condensates, aggregates and amyloids.