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Their formation is driven by liquid\u2013liquid 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.<\/jats:p>","DOI":"10.7554\/elife.111124","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T14:30:18Z","timestamp":1779978618000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.111124","source":"Crossref","is-referenced-by-count":0,"title":["Role of desolvation on biomolecular liquid\u2013liquid phase separation"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-1486-7206","authenticated-orcid":true,"given":"Kai","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01rxvg760","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physics, National Laboratory of Solid State Microstructure, Nanjing University","place":["Nanjing, 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