Relation between single-molecule properties and phase behavior of intrinsically disordered proteins

TLDR

LLPS proteins form membraneless organelles, and intrinsically disordered regions are a major driving force, suggesting a link between intramolecular and intermolecular interactions that can be exploited to relate single‑molecule properties to phase boundaries. The study aims to elucidate how different proteins contribute to LLPS assemblies by characterizing the molecular driving forces, phase boundaries, and material properties. Using a coarse‑grained framework, the authors compute the θ, Boyle, and critical temperatures for 20 diverse protein sequences. They find that these temperatures are highly correlated across sequences, a relationship that holds across different potentials and prior data, indicating that measuring θ or Boyle temperatures can predict phase behavior.

Abstract

Proteins that undergo liquid-liquid phase separation (LLPS) have been shown to play a critical role in many physiological functions through formation of condensed liquid-like assemblies that function as membraneless organelles within biological systems. To understand how different proteins may contribute differently to these assemblies and their functions, it is important to understand the molecular driving forces of phase separation and characterize their phase boundaries and material properties. Experimental studies have shown that intrinsically disordered regions of these proteins are a major driving force, as many of them undergo LLPS in isolation. Previous work on polymer solution phase behavior suggests a potential correspondence between intramolecular and intermolecular interactions that can be leveraged to discover relationships between single-molecule properties and phase boundaries. Here, we take advantage of a recently developed coarse-grained framework to calculate the θ temperature [Formula: see text], the Boyle temperature [Formula: see text], and the critical temperature [Formula: see text] for 20 diverse protein sequences, and we show that these three properties are highly correlated. We also highlight that these correlations are not specific to our model or simulation methodology by comparing between different pairwise potentials and with data from other work. We, therefore, suggest that smaller simulations or experiments to determine [Formula: see text] or [Formula: see text] can provide useful insights into the corresponding phase behavior.