{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:02:44Z","timestamp":1785420164494,"version":"3.56.0"},"posted":{"date-parts":[[2025,5,27]]},"group-title":"Biophysics","reference-count":80,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R35GM145409"],"award-info":[{"award-number":["R35GM145409"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P20GM121342"],"award-info":[{"award-number":["P20GM121342"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Aberrant aggregation of proteins into amyloid fibrils is associated with numerous neurodegenerative, systemic and metabolic diseases. Amyloidogenic proteins undergo spontaneous liquid-liquid phase separation (LLPS), rapidly forming protein-rich condensates prior to fibrillization. However, the exact effects of LLPS on amyloid aggregation remain unclear as contrasting fibrillization-promotion, inhibition and even biphasic effects have been reported in the literature. In this study, we integrate LLPS-induced heterogeneity of protein concentrations into a thermodynamic-kinetic model of amyloid aggregation. We adopt the phase transition theory and introduce protein condensates as an additional protein state alongside non-interacting monomers, oligomers and fibrils. Oligomerization and fibrillization can occur both in the protein-rich condensates and the protein-poor solution. This model allows us to derive the time evolution of different states \u2013 monomers, condensates, oligomers, and fibrils \u2013 spanning a wide range of concentrations, and determine how model parameters related to LLPS, fibrillization, and oligomerization influence fibrillization kinetics. Using this global model, we resolve the seemingly contradictory effects of LLPS on fibrillization. We expect the developed thermodynamic-kinetic model of LLPS, and amyloid aggregation will help advance our understanding, modulation, and mitigation of pathological aggregation processes in amyloid diseases.<\/jats:p>\n                <jats:sec>\n                  <jats:title>TOC<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"655849v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.23.655849","type":"posted-content","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T08:25:24Z","timestamp":1748334324000},"source":"Crossref","is-referenced-by-count":1,"title":["A Global Thermodynamic-Kinetic Model Capturing the Hallmarks of Liquid-Liquid Phase Separation and Amyloid Aggregation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5174-4729","authenticated-orcid":false,"given":"Kamal","family":"Bhandari","sequence":"first","affiliation":[{"name":"Department of Physics and Astronomy, Clemson University, South Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9799-7131","authenticated-orcid":false,"given":"Yunxiang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Clemson University, South Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1865-9814","authenticated-orcid":false,"given":"Huayuan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Clemson University, South Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2134-0859","authenticated-orcid":false,"given":"Pu Chu","family":"Ke","sequence":"additional","affiliation":[{"name":"Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1850-6336","authenticated-orcid":false,"given":"Feng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Physics and Astronomy, Clemson University, South Carolina, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041123340905000_2025.05.23.655849v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3549"},{"key":"2026041123340905000_2025.05.23.655849v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/aps.2017.28"},{"key":"2026041123340905000_2025.05.23.655849v1.3","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03349-1"},{"key":"2026041123340905000_2025.05.23.655849v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3050"},{"key":"2026041123340905000_2025.05.23.655849v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/nm1066"},{"key":"2026041123340905000_2025.05.23.655849v1.6","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"2026041123340905000_2025.05.23.655849v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-018-0075-x"},{"key":"2026041123340905000_2025.05.23.655849v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-020-0435-3"},{"key":"2026041123340905000_2025.05.23.655849v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12683-8"},{"key":"2026041123340905000_2025.05.23.655849v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41594-020-0441-5"},{"key":"2026041123340905000_2025.05.23.655849v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0060-8"},{"key":"2026041123340905000_2025.05.23.655849v1.12","first-page":"729","article-title":"Common core structure of amyloid fibrils by synchrotron X-ray diffraction 1 1Edited by F","volume":"273","year":"1997","journal-title":"E. 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