How do intrinsically disordered protein regions encode a driving force for liquid-liquid phase separation?

TL;DR

This paper explores how intrinsically disordered protein regions encode driving forces for liquid-liquid phase separation, emphasizing the importance of molecular interactions and sequence properties in cellular processes and disease.

Contribution

It introduces a conceptual framework and validated simulation models to understand the molecular interactions of disordered protein regions in phase separation.

Findings

Disordered regions can be divided into interacting and solvating parts.

Validated models can predict phase behavior based on sequence properties.

Understanding these interactions aids in identifying phase-separating proteins.

Abstract

Liquid-liquid phase separation is the mechanism underlying the formation of biomolecular condensates. Disordered protein regions often drive phase separation, but molecular interactions of disordered protein regions are not well understood, sometimes leading to the conflation that all disordered protein regions drive phase separation. Given the critical role of phase separation in many cellular processes, and that dysfunction of phase separation can lead to debilitating diseases, it is important that we understand the interactions and sequence properties underlying phase behavior. A conceptual framework that divides IDRs into interacting and solvating regions has proven particularly useful, and analytical instantiations and coarse-grained models can test our understanding of the driving forces against experimental phase behavior. Validated simulation paradigms enable the exploration of sequence space to help our understanding of how disordered protein regions can encode phase behavior, which IDRs may mediate phase separation in cells, and which IDRs are in contrast highly soluble.