Computational modeling of liquid-liquid phase separation and cargo encapsulation in self-assembling microcompartments

Liquid-liquid phase separation and proteinaceous organelles are widely employed by cells for compartmentalization. Bacterial microcompartments (BMCs) are organelles in bacteria consisting of a protein shell that assembles around a complex of enzymes and reactants. In some BMC systems, intrinsically disordered proteins have been identified as scaffolding molecules that are indispensable for assembly and cargo encapsulation. However, the specific roles of scaffolding molecules, and how assembly depends on their properties, remain unclear. We develop equilibrium theory and dynamical computational model to describe assembly of a protein shell around cargo and scaffold molecules, with cargo coalescence and encapsulation provided by scaffold-mediated interactions. Our results predict that the shell size, amount of encapsulated cargo, and assembly pathways depend sensitively on properties of the scaffold, including its length and valency of scaffold-cargo interactions. We discuss implications of these results for synthetic biology efforts to target new molecules to microcompartments interiors. More broadly, the results elucidate how cells exploit coupling between self-assembly and liquid-liquid phase separation to organize their interiors.