A modular fibrinogen model that captures the stress-strain behavior of fibrin fibers

Abstract

We tested what to our knowledge is a new computational model for fibrin fiber mechanical behavior. The model is composed of three distinct elements: the folded fibrinogen core as seen in the crystal structure, the unstructured α-C connector, and the partially folded α-C domain. Previous studies have highlighted the importance of all three regions and how they may contribute to fibrin fiber stress-strain behavior. Yet no molecular model has been computationally tested that takes into account the individual contributions of all these regions. Constant velocity, steered molecular dynamics studies at 0.025 Å/ps were conducted on the folded fibrinogen core and the α-C domain to determine their force-displacement behavior. A wormlike chain model with a persistence length of 0.8 nm (Kuhn length = 1.6 nm) was used to model the mechanical behavior of the unfolded α-C connector. The three components were combined to calculate the total stress-strain response, which was then compared to experimental data. The results show that the three-component model successfully captures the experimentally determined stress-strain behavior of fibrin fibers. The model evinces the key contribution of the α-C domains to fibrin fiber stress-strain behavior. However, conversion of the α-helical coiled coils to β-strands, and partial unfolding of the protein, may also contribute.

Figure 1

Idealized representation of α-C region under applied force where the α-connector portion of the region is modeled using a wormlike chain (WLC) and the α-domain is modeled using results from SMD simulations of the bovine α-C domain fragment (PDB: 2BAF). The ribbon represents the β-hairpin that exists on the α-C domain structure. The disulfide bond is located between cysteine residues 423 and 453.

Figure 2

Force-displacement response of the α-C domain (R420–G454) obtained using SMD (constant velocity, 0.25 Å/ps; NV ensemble).

Figure 3

Force-elongation response of fibrinogen structure (NV ensemble; constant velocity, 0.025 Å/ps).

Figure 4

Depiction of fibrin fiber network model, incorporating the effects of the fibrinogen structure (black springs), α-C connector (lines), and the α-C domains (coiled structures).

Figure 5

Graph showing experimental (black) versus three-component model prediction of axial force versus strain in fibrin fiber network with contributions from fibrinogen, α-C connector, and α-C domain for various fibril densities (5%, 30%, 50%, and 75%).

Figure 6

Graph showing percent (%) strain contribution versus axial force for the three-component model. This graph indicates the strain contributions for the fibrinogen structure, α-C connector (WLC), and α-C domain for various fibril densities.

Figure 7

Contour plot used to determine the ideal number of monomers in parallel and series for the fibrin fiber.

Figure 8

Image displaying final structures (10 total) of α-C domain subsequent to minimization and equilibration.