Insights into fibrinogen mechanics under cyclic high-strain loading

Fibrinogen plays a central role in the physiological processes of blood coagulation and, unfortunately, ischemic stroke, where it is routinely exposed to mechanical forces. In this study, we employed atomistic molecular dynamics simulations to subject fibrinogen to three cycles of high-strain loading (∼17.5-27.5%) and unloading, enabling us to probe its mechanical response under cyclic stress. To capture the effects of pulling direction and structural asymmetry, we simulated the two different fibrinogen molecules present in the crystallographic unit cell. Forces were applied to the γ1 nodule of molecule 1 and the γ2 nodule of molecule 2 in opposite directions. The simulations revealed contrasting mechanical behaviors: the γ1 nodule exhibited greater extension with partial elasticity, whereas the β-sheet-rich γ2 nodule showed higher resistance but sustained irreversible structural damage. After force relaxation, both molecules retained residual strain (6.52-15.62% across independent replicas), confirming partial irreversibility. Anisotropic normal mode analysis further identified localized reductions in stiffness linked to unfolding of secondary structural elements, including β-sheets and α-helices. Complementary Kelvin-Voigt modeling of the unloading curves further quantified these effects, showing progressive reductions in the effective spring constant (K_spec) and dashpot coefficient (C_spec) across cycles. The model captured the viscoelastic relaxation dynamics. Collectively, these findings demonstrate that fibrinogen's cyclic response is shaped by both intrinsic structural heterogeneity, revealing viscoelastic behavior with important implications for clot formation and stroke pathogenesis.