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Title: Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling

Abstract

Fibrin is the major extracellular component of blood clots and a proteinaceous hydrogel used as a versatile biomaterial. Fibrin forms branched networks built of laterally associated double-stranded protofibrils. This multiscale hierarchical structure is crucial for the extraordinary mechanical resilience of blood clots, yet the structural basis of clot mechanical properties remains largely unclear due, in part, to the unresolved molecular packing of fibrin fibers. Here the packing structure of fibrin fibers is quantitatively assessed by combining Small Angle X-ray Scattering (SAXS) measurements of fibrin reconstituted under a wide range of conditions with computational molecular modeling of fibrin protofibrils. The number, positions, and intensities of the Bragg peaks observed in the SAXS experiments were reproduced computationally based on the all-atom molecular structure of reconstructed fibrin protofibrils. Specifically, the model correctly predicts the intensities of the reflections of the 22.5 nm axial repeat, corresponding to the half-staggered longitudinal arrangement of fibrin molecules. In addition, the SAXS measurements showed that protofibrils within fibrin fibers have a partially ordered lateral arrangement with a characteristic transverse repeat distance of 13 nm, irrespective of the fiber thickness. These findings provide fundamental insights into the molecular structure of fibrin clots that underlies their biological and physical properties.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3]; ORCiD logo [4];  [5]; ORCiD logo [6];  [6]; ORCiD logo [7]; ORCiD logo [8]; ORCiD logo [6];  [9]; ORCiD logo [10]
  1. AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, UMC Utrecht
  2. KTH Royal Institute of Technology, Stockholm, Sweden, Sechenov University, Moscow 119991
  3. AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, Institute of Cell Biology
  4. Macromolecular Chemistry and New Polymeric Materials, Zernike Institute for Advanced Materials, University of Groningen, 9747 AG Groningen, The Netherlands
  5. Netherlands Organization for Scientific Research (NWO), DUBBLE CRG at the ESRF, 38000 Grenoble Cedex, France
  6. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
  7. AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, Department of Biomedical Engineering and Institute for Complex Molecular Systems
  8. Netherlands Organization for Scientific Research (NWO), DUBBLE CRG at the ESRF, 38000 Grenoble Cedex, France, Chemical Sciences Division
  9. Department of Chemistry, University of Massachusetts, Lowell, 01854, USA
  10. AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, Department of Bionanoscience
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE; European Research Council (ERC); American Heart Association; National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1647682
Alternate Identifier(s):
OSTI ID: 1661245
Grant/Contract Number:  
AC05-00OR22725; 851960; 15GRNT23150000; 13GRNT16960013; HL135254; UO1-HL116330; DMR 1505662; DMR 1505316
Resource Type:
Journal Article: Published Article
Journal Name:
Soft Matter
Additional Journal Information:
Journal Name: Soft Matter Journal Volume: 16 Journal Issue: 35; Journal ID: ISSN 1744-683X
Publisher:
Royal Society of Chemistry
Country of Publication:
United Kingdom
Language:
English

Citation Formats

Jansen, Karin A., Zhmurov, Artem, Vos, Bart E., Portale, Giuseppe, Hermida-Merino, Daniel, Litvinov, Rustem I., Tutwiler, Valerie, Kurniawan, Nicholas A., Bras, Wim, Weisel, John W., Barsegov, Valeri, and Koenderink, Gijsje H. Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling. United Kingdom: N. p., 2020. Web. doi:10.1039/D0SM00916D.
Jansen, Karin A., Zhmurov, Artem, Vos, Bart E., Portale, Giuseppe, Hermida-Merino, Daniel, Litvinov, Rustem I., Tutwiler, Valerie, Kurniawan, Nicholas A., Bras, Wim, Weisel, John W., Barsegov, Valeri, & Koenderink, Gijsje H. Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling. United Kingdom. doi:10.1039/D0SM00916D.
Jansen, Karin A., Zhmurov, Artem, Vos, Bart E., Portale, Giuseppe, Hermida-Merino, Daniel, Litvinov, Rustem I., Tutwiler, Valerie, Kurniawan, Nicholas A., Bras, Wim, Weisel, John W., Barsegov, Valeri, and Koenderink, Gijsje H. Wed . "Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling". United Kingdom. doi:10.1039/D0SM00916D.
@article{osti_1647682,
title = {Molecular packing structure of fibrin fibers resolved by X-ray scattering and molecular modeling},
author = {Jansen, Karin A. and Zhmurov, Artem and Vos, Bart E. and Portale, Giuseppe and Hermida-Merino, Daniel and Litvinov, Rustem I. and Tutwiler, Valerie and Kurniawan, Nicholas A. and Bras, Wim and Weisel, John W. and Barsegov, Valeri and Koenderink, Gijsje H.},
abstractNote = {Fibrin is the major extracellular component of blood clots and a proteinaceous hydrogel used as a versatile biomaterial. Fibrin forms branched networks built of laterally associated double-stranded protofibrils. This multiscale hierarchical structure is crucial for the extraordinary mechanical resilience of blood clots, yet the structural basis of clot mechanical properties remains largely unclear due, in part, to the unresolved molecular packing of fibrin fibers. Here the packing structure of fibrin fibers is quantitatively assessed by combining Small Angle X-ray Scattering (SAXS) measurements of fibrin reconstituted under a wide range of conditions with computational molecular modeling of fibrin protofibrils. The number, positions, and intensities of the Bragg peaks observed in the SAXS experiments were reproduced computationally based on the all-atom molecular structure of reconstructed fibrin protofibrils. Specifically, the model correctly predicts the intensities of the reflections of the 22.5 nm axial repeat, corresponding to the half-staggered longitudinal arrangement of fibrin molecules. In addition, the SAXS measurements showed that protofibrils within fibrin fibers have a partially ordered lateral arrangement with a characteristic transverse repeat distance of 13 nm, irrespective of the fiber thickness. These findings provide fundamental insights into the molecular structure of fibrin clots that underlies their biological and physical properties.},
doi = {10.1039/D0SM00916D},
journal = {Soft Matter},
issn = {1744-683X},
number = 35,
volume = 16,
place = {United Kingdom},
year = {2020},
month = {9}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at 10.1039/D0SM00916D

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