{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T14:27:21Z","timestamp":1765031241812,"version":"3.46.0"},"reference-count":40,"publisher":"IOP Publishing","issue":"5","license":[{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/publishingsupport.iopscience.iop.org\/iop-standard\/v1"},{"start":{"date-parts":[[2021,6,30]],"date-time":"2021-06-30T00:00:00Z","timestamp":1625011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/iopscience.iop.org\/info\/page\/text-and-data-mining"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","award":["PTDC\/FIS- OUT\/28210\/2017"],"award-info":[{"award-number":["PTDC\/FIS- OUT\/28210\/2017"]}]}],"content-domain":{"domain":["iopscience.iop.org"],"crossmark-restriction":false},"short-container-title":["Phys. Biol."],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Protein beta-2-microglobulin (\n                    <jats:italic>\u03b2<\/jats:italic>\n                    2m) is classically considered the causative agent of dialysis related amyloidosis, a conformational disorder that affects patients undergoing long-term hemodialysis. The wild type (WT) form, the \u0394\n                    <jats:italic>N<\/jats:italic>\n                    6 structural variant, and the D76N mutant have been extensively used as model systems of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    2m aggregation. In all of them, the native structure is stabilized by a disulfide bridge between the sulphur atoms of the cysteine residues 25 (at B strand) and 80 (at F strand), which has been considered fundamental in\n                    <jats:italic>\u03b2<\/jats:italic>\n                    2m fibrillogenesis. Here, we use extensive discrete molecular dynamics simulations of a full atomistic structure-based model to explore the role of this disulfide bridge as a modulator of the folding space of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    2m. In particular, by considering different models for the disulfide bridge, we explore the thermodynamics of the folding transition, and the formation of intermediate states that may have the potential to trigger the aggregation cascade. Our results show that the dissulfide bridge affects folding transition and folding thermodynamics of the considered model systems, although to different extents. In particular, when the interaction between the sulphur atoms is stabilized relative to the other intramolecular interactions, or even locked (i.e. permanently established), the WT form populates an intermediate state featuring a well preserved core and two unstructured termini, which was previously detected only for the D76N mutant. The formation of this intermediate state may have important implications in our understanding of\n                    <jats:italic>\u03b2<\/jats:italic>\n                    2m fibrillogenesis.\n                  <\/jats:p>","DOI":"10.1088\/1478-3975\/ac08ec","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T18:47:13Z","timestamp":1623091633000},"page":"056001","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["The folding space of protein\n                    <i>\u03b2<\/i>\n                    2-microglobulin is modulated by a single disulfide bridge"],"prefix":"10.1088","volume":"18","author":[{"given":"Jules","family":"Morand","sequence":"first","affiliation":[]},{"given":"Ana","family":"Nunes","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-2748","authenticated-orcid":false,"given":"Patr\u00edcia F N","family":"Fa\u00edsca","sequence":"additional","affiliation":[]}],"member":"266","published-online":{"date-parts":[[2021,6,30]]},"reference":[{"key":"pbac08ecbib1","doi-asserted-by":"publisher","first-page":"2276","DOI":"10.1056\/nejmoa1201356","type":"journal-article","article-title":"Hereditary systemic amyloidosis due to Asp76Asn variant \u03b22-microglobulin","volume":"366","author":"Valleix","year":"2012","journal-title":"New Engl. J. Med."},{"key":"pbac08ecbib2","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1039\/d0cp04780e","type":"journal-article","article-title":"Proline isomerization effects in the amyloidogenic protein \u03b22-microglobulin","volume":"23","author":"Maschio","year":"2021","journal-title":"Phys. Chem. Chem. Phys."},{"key":"pbac08ecbib3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-319-00882-0_1","type":"book","author":"Gomes","year":"2019"},{"key":"pbac08ecbib4","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2020.106505","type":"journal-article","article-title":"Visualizing and trapping transient oligomers in amyloid assembly pathways","volume":"268","author":"Cawood","year":"2021","journal-title":"Biophys. Chem."},{"key":"pbac08ecbib5","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/978-94-007-5416-4_7","type":"book","author":"Esposito","year":"2012"},{"key":"pbac08ecbib6","doi-asserted-by":"publisher","first-page":"278","DOI":"10.3389\/fmolb.2020.578433","type":"journal-article","volume":"7","author":"Loureiro","year":"2020","journal-title":"Front. Mol. Biosci."},{"key":"pbac08ecbib7","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1038\/nsmb1058","type":"journal-article","article-title":"Amyloid formation under physiological conditions proceeds via a native-like folding intermediate","volume":"13","author":"Jahn","year":"2006","journal-title":"Nat. Struct. Mol. Biol."},{"key":"pbac08ecbib8","doi-asserted-by":"publisher","first-page":"46714","DOI":"10.1074\/jbc.m107040200","type":"journal-article","article-title":"A partially structured species of \u03b22-microglobulin is significantly populated under physiological conditions and involved in fibrillogenesis","volume":"276","author":"Chiti","year":"2001","journal-title":"J. Biol. Chem."},{"key":"pbac08ecbib9","doi-asserted-by":"publisher","first-page":"12474","DOI":"10.1074\/jbc.ra120.014901","type":"journal-article","article-title":"The role of the IT-state in D76N \u03b22-microglobulin amyloid assembly: a crucial intermediate or an innocuous bystander?","volume":"295","author":"Smith","year":"2020","journal-title":"J. Biol. Chem."},{"key":"pbac08ecbib10","doi-asserted-by":"publisher","first-page":"30917","DOI":"10.1074\/jbc.m113.498857","type":"journal-article","article-title":"Structure, folding dynamics, and amyloidogenesis of D76N \u03b22-microglobulin","volume":"288","author":"Mangione","year":"2013","journal-title":"J. Biol. Chem."},{"key":"pbac08ecbib11","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.molcel.2010.11.028","type":"journal-article","article-title":"Conformational conversion during amyloid formation at atomic resolution","volume":"41","author":"Eichner","year":"2011","journal-title":"Mol. Cell"},{"key":"pbac08ecbib12","doi-asserted-by":"publisher","first-page":"9951","DOI":"10.1074\/jbc.r115.639799","type":"journal-article","article-title":"Systemic amyloidosis: lessons from \u03b22-microglobulin","volume":"290","author":"Stoppini","year":"2015","journal-title":"J. Biol. Chem."},{"key":"pbac08ecbib13","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.1002\/prot.25358","type":"journal-article","article-title":"A tale of two tails: the importance of unstructured termini in the aggregation pathway of \u03b22-microglobulin","volume":"85","author":"Loureiro","year":"2017","journal-title":"Proteins"},{"key":"pbac08ecbib14","doi-asserted-by":"publisher","first-page":"366","DOI":"10.3390\/biom9080366","type":"journal-article","volume":"9","author":"Loureiro","year":"2019","journal-title":"Biomolecules"},{"key":"pbac08ecbib15","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1016\/j.jmb.2012.06.020","type":"journal-article","article-title":"Identification of a conserved aggregation-prone intermediate state in the folding pathways of spc-SH3 amyloidogenic variants","volume":"422","author":"Krobath","year":"2012","journal-title":"J. Mol. Biol."},{"key":"pbac08ecbib16","doi-asserted-by":"publisher","first-page":"17256","DOI":"10.3390\/ijms140917256","type":"journal-article","article-title":"Assessing the effect of loop mutations in the folding space of \u03b22-microglobulin with molecular dynamics simulations","volume":"14","author":"Est\u00e1cio","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"pbac08ecbib17","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pcbi.1003606","type":"journal-article","volume":"10","author":"Est\u00e1cio","year":"2014","journal-title":"PLOS Comput. Biol."},{"key":"pbac08ecbib18","doi-asserted-by":"publisher","first-page":"1658","DOI":"10.1038\/s41467-018-04078-y","type":"journal-article","article-title":"Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity","volume":"9","author":"Le Marchand","year":"2018","journal-title":"Nat. Commun."},{"key":"pbac08ecbib19","doi-asserted-by":"publisher","first-page":"85102","DOI":"10.1063\/1.4747492","type":"journal-article","volume":"137","author":"Est\u00e1cio","year":"2012","journal-title":"J. Chem. Phys."},{"key":"pbac08ecbib20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1039\/9781788013253-00001","type":"journal-article","author":"Feige","year":"2018","journal-title":"Oxidative Folding of Proteins: Basic Principles, Cellular Regulation and Engineering, CHAPTER 1.1 Disulfide Bonds in Protein Folding and Stability"},{"key":"pbac08ecbib21","doi-asserted-by":"publisher","first-page":"11241","DOI":"10.1073\/pnas.1503909112","type":"journal-article","article-title":"Protein folding guides disulfide bond formation","volume":"112","author":"Qin","year":"2015","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"pbac08ecbib22","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1093\/oxfordjournals.jbchem.a003076","type":"journal-article","article-title":"The intrachain disulfide bond of 2-microglobulin is not essential for the immunoglobulin fold at neutral pH, but is essential for amyloid fibril formation at acidic pH","volume":"131","author":"Ohhashi","year":"2002","journal-title":"J. Biochem."},{"key":"pbac08ecbib23","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/s0006-291x(03)00543-6","type":"journal-article","article-title":"Amyloidogenic synthetic peptides of \u03b22-microglobulin-a role of the disulfide bond","volume":"304","author":"Hasegawa","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"pbac08ecbib24","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.jmb.2007.12.002","type":"journal-article","article-title":"Thiol compounds inhibit the formation of amyloid fibrils by \u03b22-microglobulin at neutral pH","volume":"376","author":"Yamamoto","year":"2008","journal-title":"J. Mol. Biol."},{"key":"pbac08ecbib25","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/j.jmb.2005.09.075","type":"journal-article","article-title":"A single disulfide bond differentiates aggregation pathways of \u00df2-microglobulin","volume":"354","author":"Chen","year":"2005","journal-title":"J. Mol. Biol."},{"key":"pbac08ecbib26","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1006\/jmbi.1999.2829","type":"journal-article","article-title":"The packing density in proteins: standard radii and volumes 1 1 edited by J M Thornton","volume":"290","author":"Tsai","year":"1999","journal-title":"J. Mol. Biol."},{"key":"pbac08ecbib27","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1002\/bip.1981.360200511","type":"journal-article","article-title":"Noninteracting local-structure model of folding and unfolding transition in globular proteins. I. Formulation","volume":"20","author":"Go","year":"1981","journal-title":"Biopolymers"},{"key":"pbac08ecbib28","doi-asserted-by":"publisher","first-page":"8375","DOI":"10.1021\/jp2114576","type":"journal-article","article-title":"Discrete molecular dynamics: an efficient and versatile simulation method for fine protein characterization","volume":"116","author":"Shirvanyants","year":"2012","journal-title":"J. Phys. Chem B"},{"key":"pbac08ecbib29","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/s0009-2614(99)01123-9","type":"journal-article","article-title":"Replica-exchange molecular dynamics method for protein folding","volume":"314","author":"Sugita","year":"1999","journal-title":"Chem. Phys. Lett."},{"key":"pbac08ecbib30","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1021\/ct0502864","type":"journal-article","article-title":"Use of the weighted histogram analysis method for the analysis of simulated and parallel tempering simulations","volume":"3","author":"Chodera","year":"2007","journal-title":"J. Chem. Theory Comput."},{"key":"pbac08ecbib31","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jmgm.2003.12.005","type":"journal-article","article-title":"MMTSB Tool Set: enhanced sampling and multiscale modeling methods for applications in structural biology","volume":"22","author":"Feig","year":"2004","journal-title":"J. Mol. Graphics Modelling"},{"key":"pbac08ecbib32","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1093\/jb\/mvm148","type":"journal-article","article-title":"High-resolution crystal structure of 2-microglobulin formed at pH 7.0","volume":"142","author":"Iwata","year":"2007","journal-title":"J. Biochem."},{"key":"pbac08ecbib33","doi-asserted-by":"publisher","first-page":"1312","DOI":"10.1016\/j.jmb.2009.01.013","type":"journal-article","article-title":"A generic mechanism of \u03b22-microglobulin amyloid assembly at neutral pH involving a specific proline switch","volume":"386","author":"Eichner","year":"2009","journal-title":"J. Mol. Biol."},{"key":"pbac08ecbib34","doi-asserted-by":"publisher","first-page":"3868","DOI":"10.1111\/j.1742-4658.2011.08186.x","type":"journal-article","article-title":"Understanding the complex mechanisms of \u03b22-microglobulin amyloid assembly","volume":"278","author":"Eichner","year":"2011","journal-title":"FEBS J."},{"key":"pbac08ecbib35","doi-asserted-by":"publisher","first-page":"7898","DOI":"10.1021\/acs.chemrev.6b00163","type":"journal-article","article-title":"Coarse-grained protein models and their applications","volume":"116","author":"Kmiecik","year":"2016","journal-title":"Chem. Rev."},{"key":"pbac08ecbib36","doi-asserted-by":"publisher","first-page":"248","DOI":"10.2142\/biophysico.16.0_248","type":"journal-article","article-title":"G\u014d model revisited","volume":"16","author":"Takada","year":"2019","journal-title":"Biophysics"},{"key":"pbac08ecbib37","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1074\/jbc.rev119.006794","type":"journal-article","article-title":"Successes and challenges in simulating the folding of large proteins","volume":"295","author":"Gershenson","year":"2020","journal-title":"J. Biol. Chem."},{"key":"pbac08ecbib38","doi-asserted-by":"publisher","DOI":"10.1063\/1.2977744","type":"journal-article","article-title":"Simulations of the protein folding process using topology-based models depend on the experimental structure","volume":"129","author":"Prieto","year":"2008","journal-title":"J. Chem. Phys."},{"key":"pbac08ecbib39","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1002\/jcc.21149","type":"journal-article","article-title":"Topology-based models and NMR structures in protein folding simulations","volume":"30","author":"Rey-Stolle","year":"2009","journal-title":"J. Comput. Chem."},{"key":"pbac08ecbib40","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/978-94-007-5416-4_7","type":"journal-article","article-title":"Pathological self-aggregation of b2-microglobulin: a challenge for protein biophysics","volume":"65","author":"Esposito","year":"2012","journal-title":"Subcell Biochem."}],"container-title":["Physical Biology"],"original-title":[],"link":[{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec","content-type":"text\/html","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec\/pdf","content-type":"application\/pdf","content-version":"am","intended-application":"similarity-checking"},{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T14:26:20Z","timestamp":1765031180000},"score":1,"resource":{"primary":{"URL":"https:\/\/iopscience.iop.org\/article\/10.1088\/1478-3975\/ac08ec"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,30]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,6,30]]},"published-print":{"date-parts":[[2021,9,1]]}},"URL":"https:\/\/doi.org\/10.1088\/1478-3975\/ac08ec","relation":{},"ISSN":["1478-3967","1478-3975"],"issn-type":[{"type":"print","value":"1478-3967"},{"type":"electronic","value":"1478-3975"}],"subject":[],"published":{"date-parts":[[2021,6,30]]},"assertion":[{"value":"The folding space of protein\n                      \u03b2\n                      2-microglobulin is modulated by a single disulfide bridge","name":"article_title","label":"Article Title"},{"value":"Physical Biology","name":"journal_title","label":"Journal Title"},{"value":"paper","name":"article_type","label":"Article Type"},{"value":"\u00a9 2021 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.","name":"copyright_information","label":"Copyright Information"},{"value":"2021-05-11","name":"date_received","label":"Date Received","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2021-06-07","name":"date_accepted","label":"Date Accepted","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2021-06-30","name":"date_epub","label":"Online publication date","group":{"name":"publication_dates","label":"Publication dates"}}]}}