Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures

Biomolecular condensates constitute a newly recognizedform ofspatial organization in living cells. Although many condensates arebelieved to form as a result of phase separation, the physicochemicalproperties that determine the phase behavior of heterogeneous biomolecularmixtures are only beginning to be explored. Theory and simulationprovide invaluable tools for probing the relationship between moleculardeterminants, such as protein and RNA sequences, and the emergenceof phase-separated condensates in such complex environments. Thisreview covers recent advances in the prediction and computationaldesign of biomolecular mixtures that phase-separate into many coexistingphases. First, we review efforts to understand the phase behaviorof mixtures with hundreds or thousands of species using theoreticalmodels and statistical approaches. We then describe progress in developinganalytical theories and coarse-grained simulation models to predictmultiphase condensates with the molecular detail required to makecontact with biophysical experiments. We conclude by summarizing thechallenges ahead for modeling the inhomogeneous spatial organizationof biomolecular mixtures in living cells.