Reentrant liquid condensate phase of proteins is stabilized by hydrophobic and non-ionic interactions

Nat Commun. 2021 Feb 17;12(1):1085. doi: 10.1038/s41467-021-21181-9.


Liquid-liquid phase separation of proteins underpins the formation of membraneless compartments in living cells. Elucidating the molecular driving forces underlying protein phase transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, and Annexin A11, can reenter a phase-separated regime at high salt concentrations. By bringing together experiments and simulations, we demonstrate that this reentrant phase transition in the high-salt regime is driven by hydrophobic and non-ionic interactions, and is mechanistically distinct from the low-salt regime, where condensates are additionally stabilized by electrostatic forces. Our work thus sheds light on the cooperation of hydrophobic and non-ionic interactions as general driving forces in the condensation process, with important implications for aberrant function, druggability, and material properties of biomolecular condensates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexins / chemistry
  • Cell Cycle Proteins / chemistry
  • DNA-Binding Proteins / chemistry
  • Humans
  • Hydrophobic and Hydrophilic Interactions*
  • Molecular Dynamics Simulation*
  • Phase Transition*
  • Proteins / chemistry*
  • RNA-Binding Protein FUS / chemistry
  • SOXB1 Transcription Factors / chemistry
  • Sf9 Cells
  • Spodoptera
  • Static Electricity*
  • Transcription Factors / chemistry


  • Annexins
  • BRD4 protein, human
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Proteins
  • RNA-Binding Protein FUS
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • TARDBP protein, human
  • Transcription Factors

Associated data

  • figshare/10.6084/m9.figshare.13536884