The Internal Dynamics of Fibrinogen and Its Implications for Coagulation and Adsorption

Fibrinogen is a serum multi-chain protein which, when activated, aggregates to form fibrin, one of the main components of a blood clot. Fibrinolysis controls blood clot dissolution through the action of the enzyme plasmin, which cleaves fibrin at specific locations. Although the main biochemical factors involved in fibrin formation and lysis have been identified, a clear mechanistic picture of how these processes take place is not available yet. This picture would be instrumental, for example, for the design of improved thrombolytic or anti-haemorrhagic strategies, as well as, materials with improved biocompatibility. Here, we present extensive molecular dynamics simulations of fibrinogen which reveal large bending motions centered at a hinge point in the coiled-coil regions of the molecule. This feature, likely conserved across vertebrates according to our analysis, suggests an explanation for the mechanism of exposure to lysis of the plasmin cleavage sites on fibrinogen coiled-coil region. It also explains the conformational variability of fibrinogen observed during its adsorption on inorganic surfaces and it is supposed to play a major role in the determination of the hydrodynamic properties of fibrinogen. In addition the simulations suggest how the dynamics of the D region of fibrinogen may contribute to the allosteric regulation of the blood coagulation cascade through a dynamic coupling between the a- and b-holes, important for fibrin polymerization, and the integrin binding site P1.Author Summary: Fibrinogen, a protein found in the blood of vertebrates, when activated, aggregates and forms fibrin fibers, the basis of a blood clot. Clots are broken down by the enzyme plasmin, which cuts fibrin fibers at specific places, thus helping the regulation of clot persistence. A mechanistic understanding of fibrin degradation by plasmin is still missing. An important determinant of this process might be the flexibility of fibrinogen. The flexible nature of fibrinogen is reported, for example, by the great variety of conformations observed when fibrinogen adsorbs on material surfaces. However, limits in the spatial resolution of these experiments preclude the identification of the atomistic mechanism behind this flexibility. Here, we perform computer simulations that help identifying with atomistic detail large bending motions occurring at a specific hinge on the molecule. We show how these bending motions can explain the variable conformations observed in experiments and how they help exposing sites where plasmin can cut fibrinogen. Furthermore, our simulations let us identify cooperative effects involving several distant parts of fibrinogen that may play a role in the assembly of fibrin fibers. Both the bending and the cooperative effects, thus, represent potential mechanisms for the regulation of blood clotting.