Mechanical functions of protein fibers are important in cytoskeletal support and cell motility (1), cell adhesion and formation of extracellular matrix (2), and blood clotting (3). Due to their complexity (103−105 amino acids) and large size (~40−200 nm), experimental force measurements (4,5) of their physical properties yield results that are impossible to interpret without some input from the computer-based modeling. Fibrinogen, the precursor of fibrin, provides building blocks for fibrin polymers, a scaffold of blood clots and thrombi. The mechanical properties of fibrin(ogen), which control how clots and thrombi respond to external mechanical factors, are essential for hemostasis. Yet, the complexity of fibrin(ogen) structure makes it difficult to uncover the unfolding mechanism using dynamic force measurements in vitro alone. We carried out combined experimental-theoretical studies of the mechanical properties of fibrinogen, using AFM assays and Langevin simulations on Graphics Processing Units (GPUs). A combination of the Self-Organized Polymer (SOP) model (6) and simulations on GPUs (7) makes it possible to characterize the fibrinogen nanomechanics in the experimental 0.1-1s timescale. The mechanical unraveling of fibrinogen is determined by the microscopic transitions that couple reversible extension-contraction of the coiled-coils and unfolding of the terminal γC-domains. The coiled-coils play a role of the biomolecular storage of mechanical energy to amortize an external perturbation and to transmit and distribute tension among the γC-domains. Unfolding of the γC-domains, stabilized by domain interactions with the βC-domains, result in three force signals, which are characterized by the average force of ~100 pN and peak-to-peak distance of ~30 nm. The results obtained provide important quantitative characteristics of the fibrinogen nanomechanics necessary to understand fibrin viscoelasticity at the fiber and whole clot levels.

This work has been supported by the American Heart Association grant (09SDG2460023) and by the Russian Ministry of Education grant (02−740−11−5126).

References:

1. T. P. Stossel, J. Condeelis, L. Cooley, J. H. Hartwig, A. Noegel, M. Schleicher and S. S. Shapiro, Nat Rev Mol Cell Biol 2, 138-145 (2001).
2. V. Barsegov and D. Thirumalai, Proc Natl Acad Sci USA 102, 1835-1839 (2005).
3. J. W. Weisel, Biophys Chem 112, 267-276 (2004).
4. I. Schwaiger, C. Sattler, D. R. Hostetter and M. Rief, Nature Mat 1, 232-235 (2002).
5. W. Liu, L. M. Jawerth, E. Sparks, M. R. Falvo, R. R. Hantgan, R. Superfine, S. T. Lord and M. Guthold, Science 313, 634 (2006).
6. R. I. Dima and H. Joshi, Proc Natl Acad Sci USA 105, 15743-15748 (2008).
7. A. Zhmurov, R. I. Dima, Y. Kholodov and V. Barsegov, Proteins 78, 2984-2999 (2010).