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In this work, we have employed an explicit-solvent minimal statistical mechanical model based on the lattice-gas Hamiltonian with quenched disorder\u2014which mimics crowders\u2014to investigate how protein\u2013solvent and protein\u2013crowder interactions influence condensate phase behavior and morphology. The computed phase diagrams reveal rich behavior, including upper critical solution temperature, closed-loop, and reentrant type, under varying protein\u2013solvent interactions in both equilibrium and out-of-equilibrium conditions. We elucidated the origin of the observed solvent-induced alterations of phase behavior and examined the role of protein\u2013crowder interactions in modulating the morphology and stability of the condensate. We further extended this model to binary protein mixtures, where we studied the phase behavior in the presence and absence of quenched disorder. Without disorder, the system exhibits diverse phase-separated morphologies\u2014partially wetted, fully wetted, segregative, and associative\u2014with phase boundaries delicately sensitive to protein\u2013solvent interactions. The presence of quenched disorder (or crowders) expands the range of accessible morphologies through the intricate interplay between protein\u2013protein, protein\u2013solvent, and protein\u2013crowder interactions. Overall, this work underscores that protein\u2013solvent and protein\u2013crowder interactions, together with protein\u2013protein interactions, can act as key regulatory parameters for modulating the morphology of the condensate. These insights may guide future computational and experimental studies of liquid\u2013liquid phase separation in biomolecular systems aimed at designing stimuli-responsive condensates.<\/jats:p>","DOI":"10.1063\/5.0346259","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T12:20:25Z","timestamp":1786450825000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["Liquid\u2013liquid phase separation in a minimal explicit-solvent lattice model mimicking protein solutions"],"prefix":"10.1063","volume":"165","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8122-6083","authenticated-orcid":false,"given":"Siddhartha","family":"Roy","sequence":"first","affiliation":[{"name":"Department of Physics, Indian Institute of Science Education and Research (IISER) Tirupati 1 , Tirupati, Andhra Pradesh 517619,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2243-1747","authenticated-orcid":false,"given":"Rakesh S.","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Indian Institute of Science Education and Research (IISER) Tirupati 2 , Tirupati, Andhra Pradesh 517619,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"317","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2026081107480716200_c1","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1126\/science.1223728","volume":"337","year":"2012","journal-title":"Science"},{"key":"2026081107480716200_c2","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1146\/annurev-cellbio-100913-013325","volume":"30","year":"2014","journal-title":"Annu. 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