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

TL;DR

This paper introduces a comprehensive analytical theory for heteropolymer phase separation, accounting for charge interactions and sequence heterogeneity, applicable to biological condensates and polyelectrolytes.

Contribution

It develops a novel, general theoretical framework combining density fluctuation analysis and conformational heterogeneity for heteropolymer LLPS prediction.

Findings

Applicable to diverse charged sequences from polyelectrolytes to polyampholytes

Predicts LLPS behavior as a function of pH, salt, and sequence patterning

Enables high-throughput screening of sequences for phase separation propensity

Abstract

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 are 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 novel theory that combines a random-phase-approximation treatment of polymer density fluctuations and an account of intrachain conformational heterogeneity based upon 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. The new 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 non-electrostatic interactions. Experimental ramifications of our theory are discussed.