A Simple Explicit-Solvent Model of Polyampholyte Phase Behaviors and its Ramifications for Dielectric Effects in Biomolecular Condensates

TL;DR

This study models biomolecular phase separation considering dielectric heterogeneity, revealing that the effects of low-dielectric condensates on electrostatic interactions are partially compensated, resulting in minor differences from uniform dielectric models.

Contribution

It introduces a simplified polyampholyte model with explicit solvents to analyze dielectric effects on phase behavior, combining simulations and theoretical approaches.

Findings

Simulated phase behaviors show minor differences from implicit solvent models.

Dielectric heterogeneity has a partially compensated effect on LLPS.

The model suggests only slight enhancement of LLPS due to dielectric effects.

Abstract

Biomolecular condensates such as membraneless organelles, underpinned by liquid-liquid phase separation (LLPS), are important for physiological function, with electrostatics -- among other interaction types -- being a prominent force in their assembly. Charge interactions of intrinsically disordered proteins (IDPs) and other biomolecules are sensitive to the aqueous dielectric environment. Because the relative permittivity of protein is significantly lower than that of water, the interior of an IDP condensate is a relatively low-dielectric regime, which, aside from its possible functional effects on client molecules, should facilitate stronger electrostatic interactions among the scaffold IDPs. To gain insight into this LLPS-induced dielectric heterogeneity, addressing in particular whether a low-dielectric condensed phase entails more favorable LLPS than that posited by assuming IDP electrostatic interactions are uniformly modulated by the higher dielectric constant of the pure solvent, we consider a simplified multiple-chain model of polyampholytes immersed in explicit solvents that are either polarizable or possess a permanent dipole. Notably, simulated phase behaviors of these systems exhibit only minor to moderate differences from those obtained using implicit-solvent models with a uniform relative permittivity equals to that of pure solvent. Buttressed by theoretical treatments developed here using random phase approximation and polymer field-theoretic simulations, these observations indicate a partial compensation of effects between favorable solvent-mediated interactions among the polyampholytes in the condensed phase and favorable polyampholyte-solvent interactions in the dilute phase, often netting only a minor enhancement of overall LLPS propensity from the very dielectric heterogeneity that arises from the LLPS itself. Further ramifications of this principle are discussed.