Flow molecular dynamics simulations reveal mechanosensitive regulation of von Willebrand factor through glycan-modulated autoinhibitory modules
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Abstract
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 haemostasis, 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; 1,109 residues) with native glycosylation by integrating crystallographic data and AlphaFold 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 behaviour, this work establishes a generalizable platform for dissecting protein mechanosensitivity and enabling the rational design of force-responsive therapeutics.
Graphical Abstract
Flow molecular dynamics simulations reveal that GPIbα engages the A1 domain only after the disruption of key interdomain and intermodular interactions.
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ur free, flow-based, and steered MD simulations not only substantiated previous experimental findings but also revealed previously unrecognized mechanisms of VWF mechanomodulation, including dynamic interactions between the N′AIM and C′AIM regions and the A1 domain.
Well supported. Good job!
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Insights from our flow simulations (Movie S4), which recapitulate the flow-induced unfurling of VWF and the uncoiling of N’AIM and C’AIM to expose the A1 domain (Fig. 3A), revealed that while O-linked glycans enhance steric shielding of A1 from GPIbα, they also modulate the stability of AIM–A1 interactions. Specifically, glycan-induced steric hindrance shortened the lifetimes of both N’AIM–A1 and C’AIM–A1 interactions (Fig. 3B), leading to earlier uncoiling events compared to the unglycosylated system (Fig. 3C). Importantly, the key residues mediating these interactions were conserved regardless of glycosylation status (Fig. 3D), indicating that the observed differences arise primarily from sterics 20.
With what certainty/confidence? I see the blue/red shadows in 3B but no numerical bound.
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However, at sites of vascular injury, elevated shear stress acts as a mechanical cue that triggers VWF to unfurl into an extended, conformation exposing cryptic binding sites for the platelet surface receptor glycoprotein Ibα (GPIbα)5. Remarkably, the spatial organization of VWF is highly context dependent. Within the trans-Golgi network, VWF monomers assemble via head-to-head interactions through the D’D3 domains and tail-to-tail associations via their C-terminal regions, forming higher-order multimers with a characteristic bouquet-like architecture
Good background tbh!
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Force-induced protein conformational changes govern many essential biological processes, yet their molecular mechanisms remain difficult to resolve.
Classic problem!
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