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

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.

doi:10.1039/D0SM00916D

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

Journal Article · Wed Sep 16 00:00:00 EDT 2020 · Soft Matter

DOI:https://doi.org/10.1039/D0SM00916D· OSTI ID:1647682

^[1]; Zhmurov, Artem ^[2];

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^[4]; Hermida-Merino, Daniel ^[5];

^[6]; Tutwiler, Valerie ^[6];

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^[6]; Barsegov, Valeri ^[9];

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AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, UMC Utrecht
KTH Royal Institute of Technology, Stockholm, Sweden, Sechenov University, Moscow 119991
AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, Institute of Cell Biology
Macromolecular Chemistry and New Polymeric Materials, Zernike Institute for Advanced Materials, University of Groningen, 9747 AG Groningen, The Netherlands
Netherlands Organization for Scientific Research (NWO), DUBBLE CRG at the ESRF, 38000 Grenoble Cedex, France
Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA
AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, Department of Biomedical Engineering and Institute for Complex Molecular Systems
Netherlands Organization for Scientific Research (NWO), DUBBLE CRG at the ESRF, 38000 Grenoble Cedex, France, Chemical Sciences Division
Department of Chemistry, University of Massachusetts, Lowell, 01854, USA
AMOLF, Biological Soft Matter Group, Amsterdam, The Netherlands, Department of Bionanoscience

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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE; European Research Council (ERC); American Heart Association; National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC05-00OR22725; 851960; 15GRNT23150000; 13GRNT16960013; HL135254; UO1-HL116330; DMR 1505662; DMR 1505316

OSTI ID:: 1647682

Alternate ID(s):: OSTI ID: 1661245

Journal Information:: Soft Matter, Journal Name: Soft Matter Vol. 16 Journal Issue: 35; ISSN 1744-683X

Publisher:: Royal Society of ChemistryCopyright Statement

Country of Publication:: United Kingdom

Language:: English

References (68)

Conformational Changes in Fragments D and Double-D from Human Fibrin(ogen) upon Binding the Peptide Ligand Gly-His-Arg-Pro-Amide ^† ^, ^‡ Everse, Stephen J.; Spraggon, Glen; Veerapandian, Leela Biochemistry, Vol. 38, Issue 10 https://doi.org/10.1021/bi982626w	journal	March 1999
Structure of the fibrin protofibril. Fowler, W. E.; Hantgan, R. R.; Hermans, J. Proceedings of the National Academy of Sciences, Vol. 78, Issue 8 https://doi.org/10.1073/pnas.78.8.4872	journal	August 1981
Aggregates Dramatically Alter Fibrin Ultrastructure García, Xabel; Seyve, Landry; Tellier, Zera Biophysical Journal, Vol. 118, Issue 1 https://doi.org/10.1016/j.bpj.2019.10.034	journal	January 2020
A solution for the best rotation to relate two sets of vectors Kabsch, W. Acta Crystallographica Section A, Vol. 32, Issue 5 https://doi.org/10.1107/S0567739476001873	journal	September 1976
Structure of high density fibrin networks probed with neutron scattering and rheology Weigandt, Katie M.; Pozzo, Danilo C.; Porcar, Lionel Soft Matter, Vol. 5, Issue 21 https://doi.org/10.1039/b906256d	journal	January 2009
Modeling of Fibrin Gels Based on Confocal Microscopy and Light-Scattering Data Magatti, Davide; Molteni, Matteo; Cardinali, Barbara Biophysical Journal, Vol. 104, Issue 5 https://doi.org/10.1016/j.bpj.2013.01.024	journal	March 2013
Protofibrils within fibrin fibres are packed together in a regular array Caracciolo, Giulio; De Spirito, Marco; Castellano, Agostina Thrombosis and Haemostasis, Vol. 89, Issue 04 https://doi.org/10.1055/s-0037-1613569	journal	January 2003
Radial packing, order, and disorder in collagen fibrils Hulmes, D. J.; Wess, T. J.; Prockop, D. J. Biophysical Journal, Vol. 68, Issue 5 https://doi.org/10.1016/S0006-3495(95)80391-7	journal	May 1995
Structural Basis of Interfacial Flexibility in Fibrin Oligomers Zhmurov, Artem; Protopopova, Anna D.; Litvinov, Rustem I. Structure, Vol. 24, Issue 11 https://doi.org/10.1016/j.str.2016.08.009	journal	November 2016
Buffers Strongly Modulate Fibrin Self-Assembly into Fibrous Networks Kurniawan, Nicholas A.; van Kempen, Thomas H. S.; Sonneveld, Stijn Langmuir, Vol. 33, Issue 25 https://doi.org/10.1021/acs.langmuir.7b00527	journal	June 2017
Compression-induced structural and mechanical changes of fibrin-collagen composites Kim, O. V.; Litvinov, R. I.; Chen, J. Matrix Biology, Vol. 60-61 https://doi.org/10.1016/j.matbio.2016.10.007	journal	July 2017
Mechanical Transition from α-Helical Coiled Coils to β-Sheets in Fibrin(ogen) Zhmurov, Artem; Kononova, Olga; Litvinov, Rustem I. Journal of the American Chemical Society, Vol. 134, Issue 50 https://doi.org/10.1021/ja3076428	journal	September 2012
Zerstreuung von Röntgenstrahlen Debye, P. Annalen der Physik, Vol. 351, Issue 6 https://doi.org/10.1002/andp.19153510606	journal	January 1915
Twisting of fibrin fibers limits their radial growth. Weisel, J. W.; Nagaswami, C.; Makowski, L. Proceedings of the National Academy of Sciences, Vol. 84, Issue 24 https://doi.org/10.1073/pnas.84.24.8991	journal	December 1987
High-Resolution Visualization of Fibrinogen Molecules and Fibrin Fibers with Atomic Force Microscopy Yermolenko, Ivan S.; Lishko, Valeryi K.; Ugarova, Tatiana P. Biomacromolecules, Vol. 12, Issue 2 https://doi.org/10.1021/bm101122g	journal	February 2011
Size and Density of Fibers in Fibrin and Other Filamentous Networks from Turbidimetry: Beyond a Revisited Carr–Hermans Method, Accounting for Fractality and Porosity Ferri, Fabio; Calegari, Gabriele Re; Molteni, Matteo Macromolecules, Vol. 48, Issue 15 https://doi.org/10.1021/acs.macromol.5b00893	journal	July 2015
Visualization and Mechanical Manipulations of Individual Fibrin Fibers Suggest that Fiber Cross Section Has Fractal Dimension 1.3 Guthold, M.; Liu, W.; Stephens, B. Biophysical Journal, Vol. 87, Issue 6 https://doi.org/10.1529/biophysj.104.042333	journal	December 2004
Cl− and F− anions regulate the architecture of protofibrils in fibrin gel Missori, M.; Papi, M.; Maulucci, G. European Biophysics Journal, Vol. 39, Issue 6 https://doi.org/10.1007/s00249-009-0492-3	journal	June 2009
Size and Density of Fibrin Fibers from Turbidity Carr, Marcus E.; Hermans, Jan Macromolecules, Vol. 11, Issue 1 https://doi.org/10.1021/ma60061a009	journal	January 1978
Fibrin Assembly: A Comparison of Electron Microscopic and Light Scattering Results Hantgan, Roy; Fowler, Walter; Erickson, Harold Thrombosis and Haemostasis, Vol. 44, Issue 03 https://doi.org/10.1055/s-0038-1650100	journal	January 1980
Oriented fibrin gels formed by polymerization in strong magnetic fields Torbet, J.; Freyssinet, J. -M.; Hudry-Clergeon, G. Nature, Vol. 289, Issue 5793 https://doi.org/10.1038/289091a0	journal	January 1981
The Internal Dynamics of Fibrinogen and Its Implications for Coagulation and Adsorption Köhler, Stephan; Schmid, Friederike; Settanni, Giovanni PLOS Computational Biology, Vol. 11, Issue 9 https://doi.org/10.1371/journal.pcbi.1004346	journal	September 2015
Structure of fibrin gels studied by elastic light scattering techniques: Dependence of fractal dimension, gel crossover length, fiber diameter, and fiber density on monomer concentration Ferri, Fabio; Greco, Maria; Arcòvito, Giuseppe Physical Review E, Vol. 66, Issue 1 https://doi.org/10.1103/PhysRevE.66.011913	journal	July 2002
Growth kinetics and structure of fibrin gels Ferri, F.; Greco, M.; Arcovito, G. Physical Review E, Vol. 63, Issue 3 https://doi.org/10.1103/PhysRevE.63.031401	journal	February 2001
Mechanism of Fibrin(ogen) Forced Unfolding Zhmurov, Artem; Brown, Andre E. X.; Litvinov, Rustem I. Structure, Vol. 19, Issue 11 https://doi.org/10.1016/j.str.2011.08.013	journal	November 2011
Structural Origins of Fibrin Clot Rheology Ryan, Esther A.; Mockros, Lyle F.; Weisel, John W. Biophysical Journal, Vol. 77, Issue 5 https://doi.org/10.1016/S0006-3495(99)77113-4	journal	November 1999
Strain enhancement of elastic modulus in fine fibrin clots Bale, Marsha D.; Ferry, John D. Thrombosis Research, Vol. 52, Issue 6 https://doi.org/10.1016/0049-3848(88)90129-6	journal	December 1988
Molecular Dynamics Simulations of the Initial Adsorption Stages of Fibrinogen on Mica and Graphite Surfaces Köhler, Stephan; Schmid, Friederike; Settanni, Giovanni Langmuir, Vol. 31, Issue 48 https://doi.org/10.1021/acs.langmuir.5b03371	journal	November 2015
Fibrin mechanical properties and their structural origins Litvinov, Rustem I.; Weisel, John W. Matrix Biology, Vol. 60-61 https://doi.org/10.1016/j.matbio.2016.08.003	journal	July 2017
Visualization of fibrinogen αC regions and their arrangement during fibrin network formation by high-resolution AFM Protopopova, A. D.; Barinov, N. A.; Zavyalova, E. G. Journal of Thrombosis and Haemostasis, Vol. 13, Issue 4 https://doi.org/10.1111/jth.12785	journal	January 2015
Crystal Structure of Human Fibrinogen Kollman, Justin M.; Pandi, Leela; Sawaya, Michael R. Biochemistry, Vol. 48, Issue 18 https://doi.org/10.1021/bi802205g	journal	May 2009
Nanostructure of the Fibrin Clot Yeromonahos, C.; Polack, B.; Caton, F. Biophysical Journal, Vol. 99, Issue 7 https://doi.org/10.1016/j.bpj.2010.04.059	journal	October 2010
A model of fibrin formation based on crystal structures of fibrinogen and fibrin fragments complexed with synthetic peptides Yang, Z.; Mochalkin, I.; Doolittle, R. F. Proceedings of the National Academy of Sciences, Vol. 97, Issue 26 https://doi.org/10.1073/pnas.97.26.14156	journal	December 2000
Studies of fibrin film. II. Small-angle x-ray scattering Roska, Fred J.; Ferry, John D.; Lin, J. S. Biopolymers, Vol. 21, Issue 9 https://doi.org/10.1002/bip.360210911	journal	September 1982
Real space observation of three-dimensional network structure of hydrated fibrin gel Takahashi, Atsuo; Kita, Rio; Shinozaki, Takashi Colloid and Polymer Science, Vol. 281, Issue 9 https://doi.org/10.1007/s00396-002-0839-0	journal	February 2003
Fibrin Fiber Stiffness Is Strongly Affected by Fiber Diameter, but Not by Fibrinogen Glycation Li, Wei; Sigley, Justin; Pieters, Marlien Biophysical Journal, Vol. 110, Issue 6 https://doi.org/10.1016/j.bpj.2016.02.021	journal	March 2016
Multi-scale strain-stiffening of semiflexible bundle networks Piechocka, Izabela K.; Jansen, Karin A.; Broedersz, Chase P. Soft Matter, Vol. 12, Issue 7 https://doi.org/10.1039/C5SM01992C	journal	January 2016
Complex strain induced structural changes observed in fibrin assembled in human plasma Portale, G.; Torbet, J. Nanoscale, Vol. 10, Issue 21 https://doi.org/10.1039/C8NR00353J	journal	January 2018
Mechanical Stability and Fibrinolytic Resistance of Clots Containing Fibrin, DNA, and Histones Longstaff, Colin; Varjú, Imre; Sótonyi, Péter Journal of Biological Chemistry, Vol. 288, Issue 10 https://doi.org/10.1074/jbc.M112.404301	journal	January 2013
Structural Hierarchy Governs Fibrin Gel Mechanics Piechocka, Izabela K.; Bacabac, Rommel G.; Potters, Max Biophysical Journal, Vol. 98, Issue 10 https://doi.org/10.1016/j.bpj.2010.01.040	journal	May 2010
The Fibrinogen Molecule: Its Size, Shape, and Mode of Polymerization Hall, Cecil E.; Slayter, Henry S. The Journal of Biophysical and Biochemical Cytology, Vol. 5, Issue 1 https://doi.org/10.1083/jcb.5.1.11	journal	January 1959
Visualization and identification of the structures formed during early stages of fibrin polymerization Chernysh, Irina N.; Nagaswami, Chandrasekaran; Weisel, John W. Blood, Vol. 117, Issue 17 https://doi.org/10.1182/blood-2010-07-297671	journal	April 2011
α−α Cross-Links Increase Fibrin Fiber Elasticity and Stiffness Helms, Christine C.; Ariëns, Robert A. S.; Uitte de Willige, S. Biophysical Journal, Vol. 102, Issue 1 https://doi.org/10.1016/j.bpj.2011.11.4016	journal	January 2012
Small-angle scattering by fractal systems Teixeira, J. Journal of Applied Crystallography, Vol. 21, Issue 6, p. 781-785 https://doi.org/10.1107/S0021889888000263	journal	December 1988
Lateral packing of protofibrils in fibrin fibers and fibrinogen polymers Voter, William A.; Lucaveche, Carmen; Blaurock, Allen E. Biopolymers, Vol. 25, Issue 12 https://doi.org/10.1002/bip.360251213	journal	December 1986
Fibrin Fibers Have Extraordinary Extensibility and Elasticity Liu, W. Science, Vol. 313, Issue 5787 https://doi.org/10.1126/science.1127317	journal	August 2006
The isolation of fibrinogen monomer dramatically influences fibrin polymerization Huang, Lihong; Lord, Susan T. Thrombosis Research, Vol. 131, Issue 6 https://doi.org/10.1016/j.thromres.2013.02.003	journal	June 2013
Multiscale Mechanics of Fibrin Polymer: Gel Stretching with Protein Unfolding and Loss of Water Brown, A. E. X.; Litvinov, R. I.; Discher, D. E. Science, Vol. 325, Issue 5941 https://doi.org/10.1126/science.1172484	journal	August 2009
Revealing the molecular origins of fibrin's elastomeric properties by in situ X-ray scattering Vos, Bart E.; Martinez-Torres, Cristina; Burla, Federica Acta Biomaterialia, Vol. 104 https://doi.org/10.1016/j.actbio.2020.01.002	journal	March 2020
The Structure and Function of the αC Domains of Fibrinogen Weisel, John W.; Medved, Leonid Annals of the New York Academy of Sciences, Vol. 936, Issue 1 https://doi.org/10.1111/j.1749-6632.2001.tb03517.x	journal	June 2001
Atomic Structural Models of Fibrin Oligomers Zhmurov, Artem; Protopopova, Anna D.; Litvinov, Rustem I. Structure, Vol. 26, Issue 6 https://doi.org/10.1016/j.str.2018.04.005	journal	June 2018
Basic mechanisms and regulation of fibrinolysis Longstaff, C.; Kolev, K. Journal of Thrombosis and Haemostasis, Vol. 13 https://doi.org/10.1111/jth.12935	journal	June 2015
Fibrin Networks Support Recurring Mechanical Loads by Adapting their Structure across Multiple Scales Kurniawan, Nicholas A.; Vos, Bart E.; Biebricher, Andreas Biophysical Journal, Vol. 111, Issue 5 https://doi.org/10.1016/j.bpj.2016.06.034	journal	September 2016
Recent experiments on a small-angle/wide-angle X-ray scattering beam line at the ESRF Bras, W.; Dolbnya, I. P.; Detollenaere, D. Journal of Applied Crystallography, Vol. 36, Issue 3 https://doi.org/10.1107/S002188980300400X	journal	April 2003
Identification of Fibrin Clot-Bound Plasma Proteins Talens, Simone; Leebeek, Frank W. G.; Demmers, Jeroen A. A. PLoS ONE, Vol. 7, Issue 8 https://doi.org/10.1371/journal.pone.0041966	journal	August 2012
Microfibrillar structure of type I collagen in situ Orgel, J. P. R. O.; Irving, T. C.; Miller, A. Proceedings of the National Academy of Sciences, Vol. 103, Issue 24 https://doi.org/10.1073/pnas.0502718103	journal	June 2006
Fibrin assembly. Lateral aggregation and the role of the two pairs of fibrinopeptides Weisel, J. W. Biophysical Journal, Vol. 50, Issue 6 https://doi.org/10.1016/S0006-3495(86)83552-4	journal	December 1986
The distinctive structure and composition of arterial and venous thrombi and pulmonary emboli Chernysh, Irina N.; Nagaswami, Chandrasekaran; Kosolapova, Sofia Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-59526-x	journal	March 2020
Conformational Flexibility and Self-Association of Fibrinogen in Concentrated Solutions Zuev, Yuriy F.; Litvinov, Rustem I.; Sitnitsky, Alexander E. The Journal of Physical Chemistry B, Vol. 121, Issue 33 https://doi.org/10.1021/acs.jpcb.7b05654	journal	August 2017
Spatial Ordering and Structure Factor Scaling in the Simulations of Colloid Aggregation González, Agustín E.; Ramírez-Santiago, G. Physical Review Letters, Vol. 74, Issue 7 https://doi.org/10.1103/PhysRevLett.74.1238	journal	February 1995
Small-angle x-ray scattering studies of fibrin film: Comparisons of fine and coarse films prepared with thrombin and ancrod: X-RAY SCATTERING STUDIES OF FIBRIN FILM Müller, Michael F.; Ferry, John D.; Lin, J. S. Biopolymers, Vol. 28, Issue 5 https://doi.org/10.1002/bip.360280508	journal	May 1989
Axial Period of Fibrinogen and Fibrin Stryer, Lubert; Cohen, Carolyn; Langridge, Robert Nature, Vol. 197, Issue 4869 https://doi.org/10.1038/197793a0	journal	February 1963
Reconstruction of saxs Profiles from Protein Structures Putnam, Daniel K.; Lowe, Edward W.; Meiler, Jens Computational and Structural Biotechnology Journal, Vol. 8, Issue 11 https://doi.org/10.5936/csbj.201308006	journal	August 2013
Thrombin and fibrinogen γ′ impact clot structure by marked effects on intrafibrillar structure and protofibril packing Domingues, Marco M.; Macrae, Fraser L.; Duval, Cédric Blood, Vol. 127, Issue 4 https://doi.org/10.1182/blood-2015-06-652214	journal	January 2016
Fibrinogen and fibrin: An illustrated review Pieters, Marlien; Wolberg, Alisa S. Research and Practice in Thrombosis and Haemostasis, Vol. 3, Issue 2 https://doi.org/10.1002/rth2.12191	journal	March 2019
Fibrinogen and fibrin structure and fibrin formation measured by using magnetic orientation. Freyssinet, J. M.; Torbet, J.; Hudry-Clergeon, G. Proceedings of the National Academy of Sciences, Vol. 80, Issue 6 https://doi.org/10.1073/pnas.80.6.1616	journal	March 1983
Polymerization of fibrin: specificity, strength, and stability of knob-hole interactions studied at the single-molecule level Litvinov, Rustem I.; Gorkun, Oleg V.; Owen, Scott F. Blood, Vol. 106, Issue 9 https://doi.org/10.1182/blood-2005-05-2039	journal	November 2005
Molecular and Physical Mechanisms of Fibrinolysis and Thrombolysis from Mathematical Modeling and Experiments Bannish, Brittany E.; Chernysh, Irina N.; Keener, James P. Scientific Reports, Vol. 7, Issue 1 https://doi.org/10.1038/s41598-017-06383-w	journal	August 2017

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