Emergence of multiphase condensates from a limited set of chemical building blocks

Abstract

Biomolecules composed of a limited set of chemical building blocks can co-localize into distinct, spatially segregated compartments known as biomolecular condensates. Although recent studies of intracellular condensates have shown that coexisting, immiscible condensates can form spontaneously via phase separation, it has remained unclear how coexisting and multiphase condensates assemble from chemical building blocks with limited specificity. Here we establish a connection between the interdependencies among biomolecular interactions and the thermodynamic stability of multiphase condensates. We then introduce an inverse design approach for computing the minimum interaction specificity required to assemble condensates with prescribed molecular compositions in a multicomponent biomolecular mixture. As a proof of principle, we apply our theory to design mixtures of model heteropolymers using a minimal number of distinct monomer types, and we use molecular simulations to verify that our designs produce coexisting condensates with the target molecular compositions. Our theoretical approach explains how multiphase condensates arise in naturally occurring biomolecular mixtures and provides a rational algorithm for engineering complex artificial condensates from simple chemical building blocks.