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Mechanism of collagen folding propagation studied by Molecular Dynamics simulations

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...

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Autores principales: Hartmann, Julian, Zacharias, Martin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224937/
https://www.ncbi.nlm.nih.gov/pubmed/34101748
http://dx.doi.org/10.1371/journal.pcbi.1009079
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author Hartmann, Julian
Zacharias, Martin
author_facet Hartmann, Julian
Zacharias, Martin
author_sort Hartmann, Julian
collection PubMed
description 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→Ala or Gly→Thr substitutions resulted in reduced stability and folding rates due to structural deformations interfering with folding propagation.
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spelling pubmed-82249372021-07-07 Mechanism of collagen folding propagation studied by Molecular Dynamics simulations Hartmann, Julian Zacharias, Martin PLoS Comput Biol Research Article 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→Ala or Gly→Thr substitutions resulted in reduced stability and folding rates due to structural deformations interfering with folding propagation. Public Library of Science 2021-06-08 /pmc/articles/PMC8224937/ /pubmed/34101748 http://dx.doi.org/10.1371/journal.pcbi.1009079 Text en © 2021 Hartmann, Zacharias https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hartmann, Julian
Zacharias, Martin
Mechanism of collagen folding propagation studied by Molecular Dynamics simulations
title Mechanism of collagen folding propagation studied by Molecular Dynamics simulations
title_full Mechanism of collagen folding propagation studied by Molecular Dynamics simulations
title_fullStr Mechanism of collagen folding propagation studied by Molecular Dynamics simulations
title_full_unstemmed Mechanism of collagen folding propagation studied by Molecular Dynamics simulations
title_short Mechanism of collagen folding propagation studied by Molecular Dynamics simulations
title_sort mechanism of collagen folding propagation studied by molecular dynamics simulations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224937/
https://www.ncbi.nlm.nih.gov/pubmed/34101748
http://dx.doi.org/10.1371/journal.pcbi.1009079
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