Atomic Structural Models of Fibrin Oligomers

The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. When reaching a critical length, these intermediat...

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Bibliographic Details
Published in:Structure (London) 2018-06, Vol.26 (6), p.857-868.e4
Main Authors: Zhmurov, Artem, Protopopova, Anna D., Litvinov, Rustem I., Zhukov, Pavel, Weisel, John W., Barsegov, Valeri
Format: Article
Language:English
Subjects:
fibrin
fibrin oligomers
fibrin polymerization
fibrin protofibrils
fibrinogen
GPU computing
MD simulations
multiscale modeling
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Summary:The space-filling fibrin network is a major part of clots and thrombi formed in blood. Fibrin polymerization starts when fibrinogen, a plasma protein, is proteolytically converted to fibrin, which self-assembles to form double-stranded protofibrils. When reaching a critical length, these intermediate species aggregate laterally to transform into fibers arranged into branched fibrin network. We combined multiscale modeling in silico with atomic force microscopy (AFM) imaging to reconstruct complete atomic models of double-stranded fibrin protofibrils with γ-γ crosslinking, A:a and B:b knob-hole bonds, and αC regions—all important structural determinants not resolved crystallographically. Structures of fibrin oligomers and protofibrils containing up to 19 monomers were successfully validated by quantitative comparison with high-resolution AFM images. We characterized the protofibril twisting, bending, kinking, and reversibility of A:a knob-hole bonds, and calculated hydrodynamic parameters of fibrin oligomers. Atomic structures of protofibrils provide a basis to understand mechanisms of early stages of fibrin polymerization. [Display omitted] •Atomic structures of fibrin oligomers and protofibrils are reconstructed in silico•Structural models show good agreement with high-resolution AFM images•Fibrin protofibrils are double-stranded twisted oligomers that can bend and kink•Hydrodynamic parameters of fibrin oligomers and protofibrils are calculated Zhmurov et al. used 27 relevant crystal structures to computationally reconstruct the full-atomic models of fibrin oligomers and protofibrils, which correlate with high-resolution atomic force microscopy images. The structures contain much valuable information for understanding the early stages of fibrin polymerization.
ISSN:0969-2126
1878-4186
1878-4186
DOI:10.1016/j.str.2018.04.005