{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:55:57Z","timestamp":1775264157987,"version":"3.50.1"},"reference-count":86,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Emmanuel College","award":["Derek Brewer scholarship"],"award-info":[{"award-number":["Derek Brewer scholarship"]}]},{"name":"EPSRC Doctoral Training Programme studentship","award":["EP\/T517847\/1"],"award-info":[{"award-number":["EP\/T517847\/1"]}]},{"name":"Ramon y Cajal fellowship"},{"name":"European Research Council","award":["EP\/Z002028\/1"],"award-info":[{"award-number":["EP\/Z002028\/1"]}]},{"name":"European Research Council","award":["803326"],"award-info":[{"award-number":["803326"]}]},{"name":"Ramon y Cajal fellowship","award":["RYC2021-030937-I"],"award-info":[{"award-number":["RYC2021-030937-I"]}]},{"name":"Spanish National Agency for Research","award":["PID2022-136919NA-C33)."],"award-info":[{"award-number":["PID2022-136919NA-C33)."]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"\n The deficiency of\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin protein is a genetic disorder characterized by the accumulation of misfolded protein aggregates within hepatocytes, leading to liver dysfunction. In the lung, it is found in macrophages, bronchial and epithelial alveolar cells type 2, leading to pulmonary emphysema. Despite extensive research, the precise mechanism underlying the formation of\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin inclusion bodies remain elusive. In this study, we combine equilibrium and non-equilibrium molecular dynamics simulations to elucidate the intricate process of\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin condensate formation and maturation. Our mechanistic model explains cluster accumulation\u2014specifically the onset of this pathogenesis\u2014through the emergence of phase-separated liquid-like protein droplets, which subsequently undergo inter-protein\n \u03b2<\/jats:italic>\n -sheet transitions between misfolded variants, resulting in solid-like clusters. We find that this mechanism only applies to the misfolded variant, Z-\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin, which phase-separates driven by its disordered C-terminus. In contrast, the native protein, M-\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin, shows much lower propensity to phase-separate and later form kinetically trapped aggregates. Furthermore, we explore how Z-\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin exhibits an increased capacity to form condensates near external walls with different types of interactions. Such conditions can be similar to those found within the endoplasmic reticulum membrane, where phase separation and hardening take place. Overall, our results shed light on the molecular basis of\n \n \n \n \n \n \n \u03b1<\/mml:mi>\n 1<\/mml:mn>\n <\/mml:msub>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -antitrypsin-related disorders and provide valuable microscopic insights for the development of therapeutic strategies targeting protein misfolding and aggregation-related disorders.\n <\/jats:p>","DOI":"10.1371\/journal.pcbi.1013634","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T18:43:55Z","timestamp":1763577835000},"page":"e1013634","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Molecular insights on the mechanism of \u03b11-antitrypsin condensate formation and maturation"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1160-3945","authenticated-orcid":true,"given":"Ignacio","family":"Sanchez-Burgos","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9437-6169","authenticated-orcid":true,"given":"Andres R.","family":"Tejedor","sequence":"additional","affiliation":[]},{"given":"Rosana","family":"Collepardo-Guevara","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1396-3338","authenticated-orcid":true,"given":"Jorge Bernardino","family":"de la Serna","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9530-2658","authenticated-orcid":true,"given":"Jorge R.","family":"Espinosa","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"issue":"6294","key":"pcbi.1013634.ref001","doi-asserted-by":"crossref","DOI":"10.1126\/science.aac4354","article-title":"In vivo aspects of protein folding and quality control","volume":"353","author":"D Balchin","year":"2016","journal-title":"Science."},{"key":"pcbi.1013634.ref002","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1146\/annurev-biochem-061516-045115","article-title":"Protein misfolding, amyloid formation, and human disease: a summary of progress over the last decade","volume":"86","author":"F Chiti","year":"2017","journal-title":"Annu Rev Biochem."},{"issue":"1","key":"pcbi.1013634.ref003","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/nrg3849","article-title":"Cystic fibrosis genetics: from molecular understanding to clinical application","volume":"16","author":"GR Cutting","year":"2015","journal-title":"Nat Rev Genet."},{"issue":"2","key":"pcbi.1013634.ref004","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2174\/157339906776818532","article-title":"Relationship between inflammation, insulin resistance and type 2 diabetes: \u201ccause or effect\u201d?","volume":"2","author":"JR Greenfield","year":"2006","journal-title":"Curr Diabetes Rev."},{"key":"pcbi.1013634.ref005","doi-asserted-by":"crossref","first-page":"130802","DOI":"10.1016\/j.ijbiomac.2024.130802","article-title":"Hiding in plain sight: complex interaction patterns between tau and 14-3-3\u03c2 protein variants","volume":"266","author":"R Crha","year":"2024","journal-title":"International Journal of Biological Macromolecules."},{"issue":"11","key":"pcbi.1013634.ref006","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.tibs.2019.06.008","article-title":"Nature and regulation of protein folding on the ribosome","volume":"44","author":"CA Waudby","year":"2019","journal-title":"Trends Biochem Sci."},{"key":"pcbi.1013634.ref007","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1146\/annurev-biochem-061516-044518","article-title":"Protein misfolding diseases","volume":"86","author":"FU Hartl","year":"2017","journal-title":"Annu Rev Biochem."},{"issue":"6","key":"pcbi.1013634.ref008","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/nrm3810","article-title":"The amyloid state and its association with protein misfolding diseases","volume":"15","author":"TPJ Knowles","year":"2014","journal-title":"Nat Rev Mol Cell Biol."},{"issue":"12","key":"pcbi.1013634.ref009","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/s41580-023-00647-2","article-title":"Mechanisms and pathology of protein misfolding and aggregation","volume":"24","author":"N Louros","year":"2023","journal-title":"Nat Rev Mol Cell Biol."},{"issue":"2","key":"pcbi.1013634.ref010","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/0006-291X(80)90867-0","article-title":"A surprising new protein superfamily containing ovalbumin, antithrombin-III, and alpha 1-proteinase inhibitor","volume":"95","author":"LT Hunt","year":"1980","journal-title":"Biochem Biophys Res Commun."},{"issue":"2","key":"pcbi.1013634.ref011","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.molmed.2013.10.007","article-title":"The molecular and cellular pathology of \u03b11-antitrypsin deficiency","volume":"20","author":"B Gooptu","year":"2014","journal-title":"Trends Mol Med."},{"issue":"6","key":"pcbi.1013634.ref012","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1513\/pats.201004-031AW","article-title":"The folding pathway of alpha1-antitrypsin: avoiding the unavoidable","volume":"7","author":"SP Bottomley","year":"2010","journal-title":"Proc Am Thorac Soc."},{"issue":"43","key":"pcbi.1013634.ref013","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abc1370","article-title":"The structural basis for Z \u03b11-antitrypsin polymerization in the liver","volume":"6","author":"SV Faull","year":"2020","journal-title":"Sci Adv."},{"issue":"2","key":"pcbi.1013634.ref014","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.jmb.2009.11.048","article-title":"Kinetic instability of the serpin Z alpha1-antitrypsin promotes aggregation","volume":"396","author":"AS Knaupp","year":"2010","journal-title":"J Mol Biol."},{"issue":"5","key":"pcbi.1013634.ref015","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/nsb0595-363","article-title":"The Z type variation of human alpha 1-antitrypsin causes a protein folding defect","volume":"2","author":"MH Yu","year":"1995","journal-title":"Nat Struct Biol."},{"issue":"14","key":"pcbi.1013634.ref016","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.abm2094","article-title":"Z-\u03b11-antitrypsin polymers impose molecular filtration in the endoplasmic reticulum after undergoing phase transition to a solid state","volume":"8","author":"JE Chambers","year":"2022","journal-title":"Science Advances."},{"issue":"43","key":"pcbi.1013634.ref017","doi-asserted-by":"crossref","first-page":"33663","DOI":"10.1074\/jbc.M004054200","article-title":"Pathogenic alpha 1-antitrypsin polymers are formed by reactive loop-beta-sheet A linkage","volume":"275","author":"P Sivasothy","year":"2000","journal-title":"J Biol Chem."},{"issue":"1","key":"pcbi.1013634.ref018","doi-asserted-by":"crossref","first-page":"6447","DOI":"10.1038\/s41467-021-26531-1","article-title":"Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein","volume":"12","author":"E Plessa","year":"2021","journal-title":"Nat Commun."},{"issue":"1","key":"pcbi.1013634.ref019","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1038\/s41467-019-09902-7","article-title":"Structural basis for reversible amyloids of hnRNPA1 elucidates their role in stress granule assembly","volume":"10","author":"X Gui","year":"2019","journal-title":"Nat Commun."},{"issue":"6376","key":"pcbi.1013634.ref020","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1126\/science.aan6398","article-title":"Atomic structures of low-complexity protein segments reveal kinked \u03b2 sheets that assemble networks","volume":"359","author":"MP Hughes","year":"2018","journal-title":"Science."},{"issue":"4","key":"pcbi.1013634.ref021","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41594-018-0050-8","article-title":"Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation","volume":"25","author":"F Luo","year":"2018","journal-title":"Nat Struct Mol Biol."},{"issue":"1","key":"pcbi.1013634.ref022","doi-asserted-by":"crossref","first-page":"6349","DOI":"10.1038\/s41467-020-20227-8","article-title":"The nuclear localization sequence mediates hnRNPA1 amyloid fibril formation revealed by cryoEM structure","volume":"11","author":"Y Sun","year":"2020","journal-title":"Nat Commun."},{"issue":"25","key":"pcbi.1013634.ref023","article-title":"Location and concentration of aromatic-rich segments dictates the percolating inter-molecular network and viscoelastic properties of ageing condensates","volume":"10","author":"S Blazquez","year":"2023","journal-title":"Adv Sci (Weinh)."},{"issue":"26","key":"pcbi.1013634.ref024","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2119800119","article-title":"Aging can transform single-component protein condensates into multiphase architectures","volume":"119","author":"A Garaizar","year":"2022","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"1","key":"pcbi.1013634.ref025","doi-asserted-by":"crossref","first-page":"5717","DOI":"10.1038\/s41467-022-32874-0","article-title":"Protein structural transitions critically transform the network connectivity and viscoelasticity of RNA-binding protein condensates but RNA can prevent it","volume":"13","author":"AR Tejedor","year":"2022","journal-title":"Nat Commun."},{"key":"pcbi.1013634.ref026","article-title":"Improved predictions of phase behaviour of intrinsically disordered proteins by tuning the interaction range","author":"G Tesei","year":"2022","journal-title":"bioRxiv."},{"issue":"23","key":"pcbi.1013634.ref027","doi-asserted-by":"crossref","first-page":"7830","DOI":"10.1021\/jp101759q","article-title":"Update of the charmm all-atom additive force field for lipids: validation on six lipid types","volume":"114","author":"JB Klauda","year":"2010","journal-title":"The Journal of Physical Chemistry B."},{"issue":"9","key":"pcbi.1013634.ref028","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"J Wang","year":"2004","journal-title":"J Comput Chem."},{"issue":"4","key":"pcbi.1013634.ref029","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41592-021-01098-3","article-title":"Martini 3: a general purpose force field for coarse-grained molecular dynamics","volume":"18","author":"PCT Souza","year":"2021","journal-title":"Nat Methods."},{"issue":"1","key":"pcbi.1013634.ref030","doi-asserted-by":"crossref","first-page":"8050","DOI":"10.1038\/s41467-025-62686-x","article-title":"Charged peptides enriched in aromatic residues decelerate condensate ageing driven by cross-\u03b2-sheet formation","volume":"16","author":"I Sanchez-Burgos","year":"2025","journal-title":"Nat Commun."},{"issue":"1","key":"pcbi.1013634.ref031","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/jcph.1995.1039","article-title":"Fast parallel algorithms for short-range molecular dynamics","volume":"117","author":"S Plimpton","year":"1995","journal-title":"Journal of Computational Physics."},{"key":"pcbi.1013634.ref032","doi-asserted-by":"crossref","unstructured":"Cabez\u00f3n T, De Wilde M, Herion P, Loriau R, Bollen A. Expression of human alpha 1-antitrypsin cdna in the yeast saccharomyces cerevisiae. Proceedings of the National Academy of Sciences. 1984;81(21):6594\u20138.","DOI":"10.1073\/pnas.81.21.6594"},{"issue":"6","key":"pcbi.1013634.ref033","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/s41594-018-0064-2","article-title":"Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation","volume":"25","author":"EL Guenther","year":"2018","journal-title":"Nat Struct Mol Biol."},{"issue":"1","key":"pcbi.1013634.ref034","doi-asserted-by":"crossref","first-page":"4390","DOI":"10.1038\/s41598-022-08130-2","article-title":"Kinetic interplay between droplet maturation and coalescence modulates shape of aged protein condensates","volume":"12","author":"A Garaizar","year":"2022","journal-title":"Sci Rep."},{"issue":"50","key":"pcbi.1013634.ref035","doi-asserted-by":"crossref","first-page":"17869","DOI":"10.1073\/pnas.1410159111","article-title":"Crucial role of nonspecific interactions in amyloid nucleation","volume":"111","author":"A \u0160ari\u0107","year":"2014","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"30","key":"pcbi.1013634.ref036","doi-asserted-by":"crossref","first-page":"15674","DOI":"10.1074\/jbc.M116.727826","article-title":"Molecular mechanism of z \u03b11-antitrypsin deficiency","volume":"291","author":"X Huang","year":"2016","journal-title":"Journal of Biological Chemistry."},{"issue":"12","key":"pcbi.1013634.ref037","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1016\/j.bpj.2012.05.023","article-title":"Conformational properties of the disease-causing z variant of \u03b11-antitrypsin revealed by theory and experiment","volume":"102","author":"I Kass","year":"2012","journal-title":"Biophysical Journal."},{"issue":"7873","key":"pcbi.1013634.ref038","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with alphafold","volume":"596","author":"J Jumper","year":"2021","journal-title":"Nature."},{"key":"pcbi.1013634.ref039","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1107\/S1744309111040267","article-title":"Therapeutic target-site variability in \u03b11-antitrypsin characterized at high resolution","volume":"67","author":"AOM Patschull","year":"2011","journal-title":"Acta Crystallogr Sect F Struct Biol Cryst Commun."},{"issue":"22","key":"pcbi.1013634.ref040","doi-asserted-by":"crossref","first-page":"224510","DOI":"10.1063\/1.5098551","article-title":"Breakdown of the law of rectilinear diameter and related surprises in the liquid-vapor coexistence in systems of patchy particles","volume":"150","author":"JR Espinosa","year":"2019","journal-title":"J Chem Phys."},{"issue":"1","key":"pcbi.1013634.ref041","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0009-2614(77)85375-X","article-title":"Triple-point coexistence properties of the lennard-jones system","volume":"51","author":"AJC Ladd","year":"1977","journal-title":"Chemical Physics Letters."},{"issue":"24","key":"pcbi.1013634.ref042","doi-asserted-by":"crossref","first-page":"13238","DOI":"10.1073\/pnas.1917569117","article-title":"Liquid network connectivity regulates the stability and composition of biomolecular condensates with many components","volume":"117","author":"JR Espinosa","year":"2020","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"1","key":"pcbi.1013634.ref043","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1140\/epjp\/i2013-13010-8","article-title":"Simulations: the dark side","volume":"128","author":"D Frenkel","year":"2013","journal-title":"The European Physical Journal Plus."},{"issue":"23","key":"pcbi.1013634.ref044","doi-asserted-by":"crossref","first-page":"235101","DOI":"10.1063\/5.0052813","article-title":"Finite-size shifts in simulated protein droplet phase diagrams","volume":"154","author":"D Nilsson","year":"2021","journal-title":"J Chem Phys."},{"key":"pcbi.1013634.ref045","doi-asserted-by":"crossref","first-page":"022611","DOI":"10.1103\/PhysRevE.101.022611","article-title":"Seeding approach to nucleation in the NVT ensemble: the case of bubble cavitation in overstretched Lennard Jones fluids","volume":"101","author":"P Rosales-Pelaez","year":"2020","journal-title":"Phys Rev E."},{"key":"pcbi.1013634.ref046","first-page":"2023","article-title":"Sequence-specific interactions determine viscoelasticity and aging dynamics of protein condensates","author":"I Alshareedah","year":"2023","journal-title":"bioRxiv."},{"issue":"2","key":"pcbi.1013634.ref047","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41557-021-00840-w","article-title":"Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains","volume":"14","author":"A Bremer","year":"2022","journal-title":"Nat Chem."},{"key":"pcbi.1013634.ref048","article-title":"Phase behaviour of hnrnpa1 low-complexity domain mutants described by different sequence-dependent models","author":"A Feito","year":"2024","journal-title":"bioRxiv."},{"key":"pcbi.1013634.ref049","first-page":"2023","article-title":"Universal predictive scaling laws of phase separation of prion-like low complexity domains","author":"MJ Maristany","year":"2023","journal-title":"bioRxiv."},{"issue":"2","key":"pcbi.1013634.ref050","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1021\/acscentsci.4c01617","article-title":"Chemically informed coarse-graining of electrostatic forces in charge-rich biomolecular condensates","volume":"11","author":"A R Tejedor","year":"2025","journal-title":"ACS Cent Sci."},{"issue":"23","key":"pcbi.1013634.ref051","doi-asserted-by":"crossref","first-page":"5169","DOI":"10.1016\/j.bpj.2021.11.003","article-title":"Rna modulation of transport properties and stability in phase-separated condensates","volume":"120","author":"AR Tejedor","year":"2021","journal-title":"Biophysical Journal."},{"issue":"23","key":"pcbi.1013634.ref052","doi-asserted-by":"crossref","first-page":"7189","DOI":"10.1073\/pnas.1504822112","article-title":"The disordered P granule protein LAF-1 drives phase separation into droplets with tunable viscosity and dynamics","volume":"112","author":"S Elbaum-Garfinkle","year":"2015","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"20","key":"pcbi.1013634.ref053","doi-asserted-by":"crossref","first-page":"4705","DOI":"10.3390\/molecules25204705","article-title":"Expansion of intrinsically disordered proteins increases the range of stability of liquid\u2013liquid phase separation","volume":"25","author":"A Garaizar","year":"2020","journal-title":"Molecules."},{"issue":"1","key":"pcbi.1013634.ref054","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41467-018-03255-3","article-title":"Self-interaction of NPM1 modulates multiple mechanisms of liquid-liquid phase separation","volume":"9","author":"DM Mitrea","year":"2018","journal-title":"Nat Commun."},{"issue":"1","key":"pcbi.1013634.ref055","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2015.09.015","article-title":"Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization","volume":"163","author":"A Molliex","year":"2015","journal-title":"Cell."},{"issue":"5","key":"pcbi.1013634.ref056","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1093\/nar\/gkab063","article-title":"Interplay of folded domains and the disordered low-complexity domain in mediating hnRNPA1 phase separation","volume":"49","author":"EW Martin","year":"2021","journal-title":"Nucleic Acids Res."},{"issue":"7","key":"pcbi.1013634.ref057","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1002\/pro.4108","article-title":"Electrostatic modulation of hnrnpa1 low- complexity domain liquid\u2013liquid phase separation and aggregation","volume":"30","author":"PS Tsoi","year":"2021","journal-title":"Protein Science."},{"issue":"13","key":"pcbi.1013634.ref058","doi-asserted-by":"crossref","first-page":"6825","DOI":"10.3390\/ijms25136825","article-title":"Initiation of hnrnpa1 low-complexity domain condensation monitored by dynamic light scattering","volume":"25","author":"PS Tsoi","year":"2024","journal-title":"International Journal of Molecular Sciences."},{"issue":"4","key":"pcbi.1013634.ref059","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2015.10.040","article-title":"The LC domain of hnRNPA2 adopts similar conformations in hydrogel polymers, liquid-like droplets, and nuclei","volume":"163","author":"S Xiang","year":"2015","journal-title":"Cell."},{"issue":"4","key":"pcbi.1013634.ref060","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1038\/s41588-025-02125-1","article-title":"Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency","volume":"57","author":"N Brzozowska","year":"2025","journal-title":"Nat Genet."},{"issue":"10","key":"pcbi.1013634.ref061","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1038\/s41557-023-01289-9","article-title":"The interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils","volume":"15","author":"M Linsenmeier","year":"2023","journal-title":"Nat Chem."},{"issue":"6","key":"pcbi.1013634.ref062","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.celrep.2018.01.036","article-title":"Intrinsically disordered regions can contribute promiscuous interactions to RNP granule assembly","volume":"22","author":"DSW Protter","year":"2018","journal-title":"Cell Rep."},{"key":"pcbi.1013634.ref063","article-title":"Compositional control of ageing kinetics in tdp-43 conden-sates","author":"NH Espejo","year":"2025","journal-title":"bioRxiv."},{"issue":"6391","key":"pcbi.1013634.ref064","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1126\/science.aar7366","article-title":"RNA buffers the phase separation behavior of prion-like RNA binding proteins","volume":"360","author":"S Maharana","year":"2018","journal-title":"Science."},{"issue":"5","key":"pcbi.1013634.ref065","doi-asserted-by":"crossref","DOI":"10.15252\/embj.201797452","article-title":"A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing","volume":"37","author":"A Wang","year":"2018","journal-title":"EMBO J."},{"key":"pcbi.1013634.ref066","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1146\/annurev-physchem-050317-021322","article-title":"Chemical kinetics for bridging molecular mechanisms and macroscopic measurements of amyloid fibril formation","volume":"69","author":"TCT Michaels","year":"2018","journal-title":"Annu Rev Phys Chem."},{"issue":"19","key":"pcbi.1013634.ref067","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.adu7064","article-title":"High-resolution characterization of ex vivo AAT polymers by solution-state NMR spectroscopy","volume":"11","author":"SM Lowen","year":"2025","journal-title":"Sci Adv."},{"key":"pcbi.1013634.ref068","article-title":"Ageing critically transforms the network connectivity and viscoelasticity of rna-binding protein condensates but rna can prevent it","author":"AR Tejedor","year":"2022","journal-title":"bioRxiv."},{"issue":"8","key":"pcbi.1013634.ref069","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1002\/polb.20384","article-title":"Identifying the primitive path mesh in entangled polymer liquids","volume":"43","author":"SK Sukumaran","year":"2005","journal-title":"J Polym Sci B Polym Phys."},{"key":"pcbi.1013634.ref070","doi-asserted-by":"crossref","first-page":"16051","DOI":"10.1038\/nrdp.2016.51","article-title":"\u03b11-antitrypsin deficiency","volume":"2","author":"CM Greene","year":"2016","journal-title":"Nat Rev Dis Primers."},{"issue":"5","key":"pcbi.1013634.ref071","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.cell.2015.07.047","article-title":"A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation","volume":"162","author":"A Patel","year":"2015","journal-title":"Cell."},{"issue":"8","key":"pcbi.1013634.ref072","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41557-020-0465-9","article-title":"\u03b1-Synuclein aggregation nucleates through liquid-liquid phase separation","volume":"12","author":"S Ray","year":"2020","journal-title":"Nat Chem."},{"issue":"3","key":"pcbi.1013634.ref073","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41580-020-00326-6","article-title":"Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing","volume":"22","author":"S Alberti","year":"2021","journal-title":"Nat Rev Mol Cell Biol."},{"issue":"7","key":"pcbi.1013634.ref074","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.tibs.2020.12.005","article-title":"FUS and TDP-43 phases in health and disease","volume":"46","author":"B Portz","year":"2021","journal-title":"Trends Biochem Sci."},{"key":"pcbi.1013634.ref075","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198520597.001.0001","volume-title":"Polymer physics","author":"M Rubinstein","year":"2003"},{"key":"pcbi.1013634.ref076","article-title":"Time-dependent material properties of aging biomolecular condensates from different viscoelasticity measurements in molecular dynamics simulations","author":"AR Tejedor","year":"2023","journal-title":"The Journal of Physical Chemistry B."},{"issue":"15","key":"pcbi.1013634.ref077","doi-asserted-by":"crossref","DOI":"10.1063\/1.3491098","article-title":"Efficient on the fly calculation of time correlation functions in computer simulations","volume":"133","author":"J Ram\u00edrez","year":"2010","journal-title":"The Journal of Chemical Physics."},{"issue":"449","key":"pcbi.1013634.ref078","first-page":"11","article-title":"Introduction to modern statistical mechanics","volume":"5","author":"D Chandler","year":"1987","journal-title":"Oxford University Press."},{"key":"pcbi.1013634.ref079","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.bbamem.2015.12.032","article-title":"Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms","volume":"1858","author":"T Mori","year":"2016","journal-title":"Biochim Biophys Acta."},{"issue":"2","key":"pcbi.1013634.ref080","doi-asserted-by":"crossref","first-page":"214","DOI":"10.3390\/biom10020214","article-title":"Structural changes of sarco\/endoplasmic reticulum Ca2+-ATPase induced by rutin arachidonate: a molecular dynamics study","volume":"10","author":"Y Rodr\u00edguez","year":"2020","journal-title":"Biomolecules."},{"issue":"3","key":"pcbi.1013634.ref081","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1073\/pnas.0504860102","article-title":"Experiment and theory for heterogeneous nucleation of protein crystals in a porous medium","volume":"103","author":"NE Chayen","year":"2006","journal-title":"Proc Natl Acad Sci U S A."},{"issue":"50","key":"pcbi.1013634.ref082","doi-asserted-by":"crossref","first-page":"13971","DOI":"10.1021\/jp0741612","article-title":"Influence of the roughness, topography, and physicochemical properties of chemically modified surfaces on the heterogeneous nucleation of protein crystals","volume":"111","author":"Y-X Liu","year":"2007","journal-title":"J Phys Chem B."},{"issue":"47","key":"pcbi.1013634.ref083","doi-asserted-by":"crossref","first-page":"9625","DOI":"10.1039\/C9SM01142K","article-title":"Heterogeneous versus homogeneous crystal nucleation of hard spheres","volume":"15","author":"JR Espinosa","year":"2019","journal-title":"Soft Matter."},{"issue":"3","key":"pcbi.1013634.ref084","doi-asserted-by":"crossref","first-page":"034501","DOI":"10.1063\/1.4939641","article-title":"Seeding approach to crystal nucleation","volume":"144","author":"JR Espinosa","year":"2016","journal-title":"J Chem Phys."},{"key":"pcbi.1013634.ref085","doi-asserted-by":"crossref","first-page":"7057","DOI":"10.1103\/PhysRevE.60.7057","article-title":"Interfacial free energy of hard-sphere fluids and solids near a hard wall","volume":"60","author":"M Heni","year":"1999","journal-title":"Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics."},{"issue":"3","key":"pcbi.1013634.ref086","doi-asserted-by":"crossref","DOI":"10.15252\/emmm.202013167","article-title":"Development of a small molecule that corrects misfolding and increases secretion of Z \u03b11-antitrypsin","volume":"13","author":"DA Lomas","year":"2021","journal-title":"EMBO Mol Med."}],"container-title":["PLOS Computational 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