Solubility product constant directs the formation of biomolecular condensates

Biomolecular condensates, formed by liquid-liquid phase separation (LLPS), are important cellular structures. Using stochastic network-free kinetic models, we establish a physical-chemical basis for the concentration threshold of heterotypic multivalent molecules required for LLPS. We associate phase separation with a bimodal partitioning of the cluster distribution into small oligomers vs. huge polymers. The simulations reveal that LLPS obeys the solubility product constant (Ksp): the product of monomer concentrations, accounting for ideal stoichiometries, does not exceed a threshold no matter how much additional monomer is added to the system – additional monomer is funneled into large clusters. The Ksp applies over a range of valencies and stoichiometries. However, consistent with the importance of disordered domains for LLPS, removing flexible linker domains funnels valency-matched monomers into a “dimer trap”, and Ksp no longer defines a threshold for large cluster formation. We propose Ksp as a new tool for elucidating biomolecular condensate biophysics.