A unified analytical theory of heteropolymers for sequence-specific phase behaviors of polyelectrolytes and polyampholytes

The physical chemistry of liquid-liquid phase separation (LLPS) of polymer solutions bears directly on the assembly of biologically functional droplet-like bodies from proteins and nucleic acids. These biomolecular condensates include certain extracellular materials and intracellular compartments that are characterized as membraneless organelles. Analytical theories are a valuable, computationally efficient tool for addressing general principles. LLPS of neutral homopolymers is quite well described by theory, but it has been a challenge to develop general theories for the LLPS of heteropolymers involving charge-charge interactions. Here, we present a theory that combines a random-phase-approximation treatment of polymer density fluctuations and an account of intrachain conformational heterogeneity based on renormalized Kuhn lengths to provide predictions of LLPS properties as a function of pH, salt, and charge patterning along the chain sequence. Advancing beyond more limited analytical approaches, our LLPS theory is applicable to a wide variety of charged sequences ranging from highly charged polyelectrolytes to neutral or nearly neutral polyampholytes. This theory should be useful in high-throughput screening of protein and other sequences for their LLPS propensities and can serve as a basis for more comprehensive theories that incorporate nonelectrostatic interactions. Experimental ramifications of our theory are discussed. Published under license by AIP Publishing.