Decoding the physical principles of biomolecular phase separation*

Cells possess non-membrane bound compartments, many of which form via liquid-liquid phase separation. Unlike conventional phase separation, e.g. the demixing of oil and water, the underlying interactions that drive biomolecular phase separation typically involve strong specific binding, often among multiple components. What are the physical principles that govern phase separation in such complex systems? We combined coarse-grained molecular dynamics simulations and analytical theory to investigate how the macroscopic phase boundaries and physical properties of condensates depend on the microscopic properties of the polymers and the concentration ratio between polymer species. We discovered novel phenomena in two-component associating polymer systems – prototypes of many membraneless organelles – including suppression of phase separation at equal polymer stoichiometry and a super-Arrhenius increase of condensate viscosity with binding strength. These results provide insight into the factors that control the formation and physical properties of condensates, and suggest potential cellular strategies for condensate regulation.