Role of desolvation on biomolecular liquid-liquid phase separation.
- 1Department of Physics, National Laboratory of Solid State Microstructure, Nanjing University, Nanjing, China.
- 2Wenzhou Key Laboratory of Biophysics, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, China.
- 3Jiangsu Key Laboratory for Cardiovascular Information and Health Engineering Medicine, Department of Cardiology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, China.
Abstract
Biomolecular condensates play essential roles in cellular organization and are implicated in diverse pathological processes. Their formation is driven by liquid-liquid phase separation (LLPS), a process that requires coordinated multistep desolvation of biomolecular chains and multivalent inter-chain interactions. Although coarse-grained (CG) models with implicit solvent are widely used to probe LLPS thermodynamics and kinetics, they typically neglect water-mediated desolvation effects, limiting their accuracy and mechanistic interpretability. Here, guided by all-atom simulations and experimental measurements, we develop a desolvation-aware implicit-solvent CG model by incorporating residue-level desolvation terms directly into the pairwise energy function, and apply it to investigate LLPS of intrinsically disordered proteins. Incorporating these desolvation interactions reshapes the phase diagram, alleviating dense-phase overcompaction. Notably, we observe an approximately linear correlation between the temperature gap (simulation temperature relative to the critical point) and the extent of conformational expansion accompanying the dilute-to-dense phase transition, a result further supported by theoretical analysis. We also find that desolvation barriers slow early density-fluctuation growth and shorten transient kinetic arrest, whereas solvent-separated contact interactions exert the opposite effects. Both terms further modulate chain mobility within mature condensates through competing packing and energy-landscape effects. Together, this framework enables an efficient representation of desolvation in CG simulations and reveals how desolvation energetics shape both the thermodynamic landscape and kinetic properties of biomolecular LLPS.
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BibTeX
@article{zhang2026role,
title = {{Role of desolvation on biomolecular liquid-liquid phase separation.}},
author = {Kai Zhang and Zhiyu Peng and Wenfei Li and Wei Wang},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.111124},
url = {https://europepmc.org/article/MED/42853069},
note = {CC BY},
}
RIS
TY - JOUR
TI - Role of desolvation on biomolecular liquid-liquid phase separation.
AU - Kai Zhang
AU - Zhiyu Peng
AU - Wenfei Li
AU - Wei Wang
PY - 2026
DA - 2026/10/09
JO - ELife
DO - 10.7554/elife.111124
UR - https://europepmc.org/article/MED/42853069
AB - Biomolecular condensates play essential roles in cellular organization and are implicated in diverse pathological processes. Their formation is driven by liquid-liquid phase separation (LLPS), a process that requires coordinated multistep desolvation of biomolecular chains and multivalent inter-chain interactions. Although coarse-grained (CG) models with implicit solvent are widely used to probe LLPS thermodynamics and kinetics, they typically neglect water-mediated desolvation effects, limiting their accuracy and mechanistic interpretability. Here, guided by all-atom simulations and experimental measurements, we develop a desolvation-aware implicit-solvent CG model by incorporating residue-level desolvation terms directly into the pairwise energy function, and apply it to investigate LLPS of intrinsically disordered proteins. Incorporating these desolvation interactions reshapes the phase diagram, alleviating dense-phase overcompaction. Notably, we observe an approximately linear correlation between the temperature gap (simulation temperature relative to the critical point) and the extent of conformational expansion accompanying the dilute-to-dense phase transition, a result further supported by theoretical analysis. We also find that desolvation barriers slow early density-fluctuation growth and shorten transient kinetic arrest, whereas solvent-separated contact interactions exert the opposite effects. Both terms further modulate chain mobility within mature condensates through competing packing and energy-landscape effects. Together, this framework enables an efficient representation of desolvation in CG simulations and reveals how desolvation energetics shape both the thermodynamic landscape and kinetic properties of biomolecular LLPS.
SN - 2050-084X
ER -