{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T16:27:42Z","timestamp":1777739262191,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009079","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000}}],"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB1035\/B05"],"award-info":[{"award-number":["SFB1035\/B05"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Collagen forms a characteristic triple helical structure and plays a central role for stabilizing the extra-cellular matrix. After a C-terminal nucleus formation folding proceeds to form long triple-helical fibers. The molecular details of triple helix folding process is of central importance for an understanding of several human diseases associated with misfolded or unstable collagen fibrils. However, the folding propagation is too rapid to be studied by experimental high resolution techniques. We employed multiple Molecular Dynamics simulations starting from unfolded peptides with an already formed nucleus to successfully follow the folding propagation in atomic detail. The triple helix folding was found to propagate involving first two chains forming a short transient template. Secondly, three residues of the third chain fold on this template with an overall mean propagation of ~75 ns per unit. The formation of loops with multiples of the repeating unit was found as a characteristic misfolding event especially when starting from an unstable nucleus. Central Gly\u2192Ala or Gly\u2192Thr substitutions resulted in reduced stability and folding rates due to structural deformations interfering with folding propagation.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009079","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T18:43:41Z","timestamp":1623177821000},"page":"e1009079","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Mechanism of collagen folding propagation studied by Molecular Dynamics simulations"],"prefix":"10.1371","volume":"17","author":[{"given":"Julian","family":"Hartmann","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5163-2663","authenticated-orcid":true,"given":"Martin","family":"Zacharias","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"pcbi.1009079.ref001","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1146\/annurev.biochem.77.032207.120833","article-title":"Collagen Structure and Stability","volume":"78","author":"MD Shoulders","year":"2009","journal-title":"Annu Rev Biochem"},{"key":"pcbi.1009079.ref002","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/174269c0","article-title":"Structure of Collagen","volume":"174","author":"GN Ramachandran","year":"1954","journal-title":"Nature"},{"key":"pcbi.1009079.ref003","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/176915a0","article-title":"The Structure of Collagen","volume":"176","author":"A Rich","year":"1955","journal-title":"Nature"},{"key":"pcbi.1009079.ref004","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/176501a0","article-title":"Structure of poly-L-proline","volume":"176","author":"P Cowan","journal-title":"Nature"},{"key":"pcbi.1009079.ref005","doi-asserted-by":"crossref","first-page":"4273","DOI":"10.1073\/pnas.070050097","article-title":"Destabilization of osteogenesis imperfecta collagen-like model peptides correlates with the identity of the residue replacing glycine","volume":"97","author":"K Beck","year":"2000","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1009079.ref006","first-page":"208","article-title":"Collagen Defect of Bone in Osteogenesis Imperfecta (Type I): An Electron Microscopic Study","volume":"183","author":"CJP Jones","year":"1984","journal-title":"Clin Orthop Relat Res"},{"key":"pcbi.1009079.ref007","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1002\/(SICI)1096-8628(19980428)77:1<31::AID-AJMG8>3.0.CO;2-O","article-title":"Ehlers-Danlos syndromes: Revised nosology, Villefranche, 1997","volume":"77","author":"P Beighton","year":"1998","journal-title":"Am J Med Genet"},{"key":"pcbi.1009079.ref008","first-page":"545","article-title":"Sequence and localization of a partial cDNA encoding the human alpha 3 chain of type IV collagen","volume":"49","author":"KE Morrison","year":"1991","journal-title":"Am J Hum Genet"},{"key":"pcbi.1009079.ref009","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/ki.1992.276","article-title":"The pathogenesis of Alport syndrome involves type IV collagen molecules containing the \u03b13(IV) chain: Evidence from anti-GBM nephritis after renal transplantation","volume":"42","author":"BG Hudson","year":"1992","journal-title":"Kidney Int"},{"key":"pcbi.1009079.ref010","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1098\/rstb.2000.0761","article-title":"Nuclear magnetic resonance characterization of peptide models of collagen\u2013folding diseases","volume":"356","author":"A Buevich","year":"2001","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"pcbi.1009079.ref011","doi-asserted-by":"crossref","first-page":"46890","DOI":"10.1074\/jbc.M407061200","article-title":"Transformation of the Mechanism of Triple-helix Peptide Folding in the Absence of a C-terminal Nucleation Domain and Its Implications for Mutations in Collagen Disorders","volume":"279","author":"AV Buevich","year":"2004","journal-title":"J Biol Chem"},{"key":"pcbi.1009079.ref012","doi-asserted-by":"crossref","first-page":"13897","DOI":"10.1073\/pnas.0505141102","article-title":"Collagen triple-helix formation in all-trans chains proceeds by a nucleation\/growth mechanism with a purely entropic barrier","volume":"102","author":"A Bachmann","year":"2005","journal-title":"Proc Natl Acad Sci"},{"key":"pcbi.1009079.ref013","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1006\/jmbi.2002.5439","article-title":"Nucleation and propagation of the collagen triple helix in single-chain and trimerized peptides: transition from third to first order kinetics11Edited by R. Huber","volume":"317","author":"S Boudko","year":"2002","journal-title":"J Mol Biol"},{"key":"pcbi.1009079.ref014","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1073\/pnas.72.8.3009","article-title":"Interchain disulfide bonds in procollagen are located in a large nontriple-helical COOH-terminal domain","volume":"72","author":"PH Byers","year":"1975","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009079.ref015","doi-asserted-by":"crossref","first-page":"13243","DOI":"10.1073\/pnas.1208072109","article-title":"Molecular basis for the action of the collagen-specific chaperone Hsp47\/SERPINH1 and its structure-specific client recognition","volume":"109","author":"C Widmer","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pcbi.1009079.ref016","first-page":"193","article-title":"Molecular dynamics simulations of the full triple helical region of collagen type I provide an atomic scale view of the protein\u2019s regional heterogeneity","author":"DL Bodian","year":"2011","journal-title":"Pac Symp Biocomput Pac Symp Biocomput"},{"key":"pcbi.1009079.ref017","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.matbio.2011.03.010","article-title":"Molecular simulations predict novel collagen conformations during cross-link loading","volume":"30","author":"JW Bourne","year":"2011","journal-title":"Matrix Biol"},{"key":"pcbi.1009079.ref018","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1039\/c2ra01047j","article-title":"Osteogenesis imperfecta mutations lead to local tropocollagen unfolding and disruption of H-bond network","volume":"2","author":"A Gautieri","year":"2012","journal-title":"RSC Adv"},{"key":"pcbi.1009079.ref019","doi-asserted-by":"crossref","first-page":"4108","DOI":"10.1529\/biophysj.107.108100","article-title":"Folding and Misfolding of the Collagen Triple Helix: Markov Analysis of Molecular Dynamics Simulations","volume":"93","author":"S Park","year":"2007","journal-title":"Biophys J"},{"key":"pcbi.1009079.ref020","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1110\/ps.062124606","article-title":"The folding mechanism of collagen-like model peptides explored through detailed molecular simulations","volume":"15","author":"CM Stultz","year":"2006","journal-title":"Protein Sci"},{"key":"pcbi.1009079.ref021","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.jmbbm.2018.07.009","article-title":"Steered molecular dynamics characterization of the elastic modulus and deformation mechanisms of single natural tropocollagen molecules","volume":"86","author":"M Tang","year":"2018","journal-title":"J Mech Behav Biomed Mater"},{"key":"pcbi.1009079.ref022","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.semcdb.2016.11.005","article-title":"Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone","volume":"62","author":"S Ito","year":"2017","journal-title":"Semin Cell Dev Biol"},{"key":"pcbi.1009079.ref023","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1074\/jbc.TM118.002812","article-title":"Roles of the endoplasmic reticulum\u2013resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease","volume":"294","author":"S Ito","year":"2019","journal-title":"J Biol Chem"},{"key":"pcbi.1009079.ref024","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jmb.2006.07.014","article-title":"Conformational effects of Gly-X-Gly interruptions in the collagen triple helix","volume":"362","author":"J Bella","year":"2006","journal-title":"J Mol Biol"},{"key":"pcbi.1009079.ref025","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1126\/science.7695699","article-title":"Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution","volume":"266","author":"J Bella","year":"1994","journal-title":"Science"},{"key":"pcbi.1009079.ref026","doi-asserted-by":"crossref","first-page":"6539","DOI":"10.1021\/bi020070d","article-title":"Folding and Conformational Consequences of Glycine to Alanine Replacements at Different Positions in a Collagen Model Peptide","volume":"41","author":"M Bhate","year":"2002","journal-title":"Biochemistry"},{"key":"pcbi.1009079.ref027","doi-asserted-by":"crossref","first-page":"5960","DOI":"10.1021\/acs.jctc.0c00524","article-title":"Simple Model of Protein Energetics To Identify Ab Initio Folding Transitions from All-Atom MD Simulations of Proteins","volume":"16","author":"M Meli","year":"2020","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1009079.ref028","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/bip.22048","article-title":"Crystal structure of (Gly-Pro-Hyp)9: Implications for the collagen molecular model","volume":"97","author":"K Okuyama","year":"2012","journal-title":"Biopolymers"},{"key":"pcbi.1009079.ref029","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1002\/jcc.20290","article-title":"The Amber biomolecular simulation programs","volume":"26","author":"DA Case","year":"2005","journal-title":"J Comput Chem"},{"key":"pcbi.1009079.ref030","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1021\/acs.jctc.5b00255","article-title":"ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB","volume":"11","author":"JA Maier","year":"2015","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1009079.ref031","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1021\/jz501780a","article-title":"Building Water Models: A Different Approach","volume":"5","author":"S Izadi","year":"2014","journal-title":"J Phys Chem Lett"},{"key":"pcbi.1009079.ref032","doi-asserted-by":"crossref","first-page":"1864","DOI":"10.1021\/ct5010406","article-title":"Long-Time-Step Molecular Dynamics through Hydrogen Mass Repartitioning","volume":"11","author":"CW Hopkins","year":"2015","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1009079.ref033","doi-asserted-by":"crossref","first-page":"3878","DOI":"10.1021\/ct400314y","article-title":"Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 2. Explicit Solvent Particle Mesh Ewald","volume":"9","author":"R Salomon-Ferrer","year":"2013","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1009079.ref034","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1021\/ct200909j","article-title":"Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 1. Generalized Born","volume":"8","author":"AW G\u00f6tz","year":"2012","journal-title":"J Chem Theory Comput"},{"key":"pcbi.1009079.ref035","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1016\/0021-9991(77)90098-5","article-title":"Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes","volume":"23","author":"J-P Ryckaert","year":"1977","journal-title":"J Comput Phys"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009079","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T00:00:00Z","timestamp":1624492800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009079","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T17:45:29Z","timestamp":1624556729000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009079"}},"subtitle":[],"editor":[{"given":"Alexander","family":"MacKerell","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,6,8]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009079","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1009079","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,8]]}}}