Force-induced protein conformational changes govern many essential biological processes, yet their molecular mechanisms remain difficult to resolve. Von Willebrand factor (VWF), a central regulator of hemostasis, is activated by hydrodynamic forces in blood flow, but how mechanical signals propagate across its multidomain architecture is poorly understood. Here, we use flow molecular dynamics (FMD), a simulation framework that applies fluid forces via controlled solvent flow to interrogate mechanosensitive proteins. Using VWF as a model system, we reconstructed the complete mechanomodule (D′D3–A1–A2–A3; 1110 residues) with native glycosylation by integrating crystallographic data and ColabFold predictions. FMD simulations capture a force-driven transition from a compact, autoinhibited “bird's nest” ensemble to an extended, activated state, revealing asymmetric autoinhibitory strengths within the N′AIM and C′AIM modules of the A1 domain. By directly linking static structures to dynamic, force-regulated behavior, this work establishes a generalizable platform for dissecting protein mechanosensitivity and enabling the rational design of force-responsive therapeutics.
Louis et al. (Wed,) studied this question.