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 dropletlike 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.The physical chemistry of liquid-liquid phase separation (LLPS) of polymer solutions bears directly on the assembly of biologically functional dropletlike 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 L...