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Here we employ constant-pH molecular dynamics simulations to quantify residue-specific protonation behavior in native monomeric insulin and in fibrils of increasing size. While the native monomer exhibits largely uncoupled titration with modest pKa perturbations, conversion to the fibrillar fold induces systematic upshifts of acidic residues driven by partial desolvation and reduced dielectric screening. Upon self-association, strong electrostatic coupling emerges between neighboring glutamate residues aligned along the fibril axis, giving rise to cooperative and multistep titration behavior. In fibril assemblies, central residues consistently deprotonate first, despite residing in partially solvent-shielded environments within the fibril core, indicating that collective electrostatic frustration overrides simple solvent accessibility effects. This cooperative charge redistribution is accompanied by a progressive loss of intermonomer contacts, revealing pH-dependent weakening of fibril cohesion. Together, our results demonstrate that insulin fibrillation is governed by collective electrostatics that arises only after conformational rearrangement and assembly, providing an atomistic framework for understanding pH-regulated amyloid stability.<\/jats:p>","DOI":"10.1021\/acsphyschemau.6c00045","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T09:25:28Z","timestamp":1782293128000},"page":"1102-1114","source":"Crossref","is-referenced-by-count":1,"title":["Characterization\nof the pH-Dependent Stabilizing Forces\nof Insulin\u2019s Native and Fibril States"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9629-9195","authenticated-orcid":true,"given":"Stefan","family":"Herv\u00f8-Hansen","sequence":"first","affiliation":[{"name":"The University of Osaka , , , ,","place":["Toyonaka, Osaka, Japan, 560-8531"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7176-441X","authenticated-orcid":true,"given":"Nobuyuki","family":"Matubayasi","sequence":"additional","affiliation":[{"name":"The University of Osaka , , , ,","place":["Toyonaka, Osaka, Japan, 560-8531"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"2026092310063558300_cit1","volume-title":"Lehninger Principles\nof Biochemistry","author":"Nelson","year":"2012","edition":"6"},{"key":"2026092310063558300_cit2","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1007\/s00125-020-05192-7","article-title":"The making of insulin\nin health and disease","volume":"63","author":"Vasiljevic\u0301","year":"2020","journal-title":"Diabetologia"},{"key":"2026092310063558300_cit3","doi-asserted-by":"publisher","first-page":"136","DOI":"10.2337\/dc16-2042","article-title":"Diabetic Neuropathy:\nA Position Statement by the American Diabetes Association","volume":"40","author":"Pop-Busui","year":"2017","journal-title":"Diabetes Care"},{"key":"2026092310063558300_cit4","volume-title":"Classification\nof Diabetes Mellitus","year":"2019"},{"key":"2026092310063558300_cit5","doi-asserted-by":"publisher","first-page":"2951","DOI":"10.1021\/acs.molpharmaceut.3c00013","article-title":"Chemometrics in Protein\nFormulation: Stability Governed by Repulsion\nand Protein Unfolding","volume":"20","author":"Kulakova","year":"2023","journal-title":"Mol. Pharmaceutics"},{"key":"2026092310063558300_cit6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1021\/ja01206a030","article-title":"A Fibrous\nModification of Insulin. I. The Heat Precipitate of Insulin","volume":"68","author":"Waugh","year":"1946","journal-title":"J. Am. Chem. Soc."},{"key":"2026092310063558300_cit7","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1021\/js960297s","article-title":"Toward Understanding\nInsulin Fibrillation","volume":"86","author":"Brange","year":"1997","journal-title":"J. Pharm. Sci."},{"key":"2026092310063558300_cit8","doi-asserted-by":"publisher","first-page":"21449","DOI":"10.1074\/jbc.M314141200","article-title":"Mechanism of Insulin\nFibrillation","volume":"279","author":"Hua","year":"2004","journal-title":"J. Biol. 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