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<p>The conformational activation of α<sub>IIb</sub>β<sub>3</sub>integrin is crucial for platelet aggregation, a central event in hemostasis and thrombosis. Although activation can be triggered by extracellular arginine-glycine-aspartic acid (RGD)-containing ligands as well as mechanical forces, how these biochemical and mechanical cues exactly govern the structural dynamics of α<sub>IIb</sub>β<sub>3</sub>remains unclear. Here, using all-atom molecular dynamics simulations, we show that mechanical force and RGD binding promote activation α<sub>IIb</sub>β<sub>3</sub>through distinct mechanisms. Mechanical force applied to the RGD-binding site induces long-range, correlated motions of distant parts of the receptor, facilitating head–leg separation. In contrast, RGD binding increases localized, non-correlated fluctuations that weaken leg coordination but do not generate long-range motions. Despite these differences, both cues stabilize the open, extended conformation of α<sub>IIb</sub>β<sub>3</sub>. Together, these findings suggest that mechanical and biochemical stimuli play&#xa0;complementary yet distinct&#xa0;roles in integrin conformational activation. A balance between global coordination and local fluctuations likely governs integrin activation in complex environments where the dominance of mechanical or biochemical cues could lead to distinct activation pathways and functional outcomes.</p>

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All-atom simulations reveal distinct pathways for αIIbβ3 activation by biochemical vs. mechanical cues

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Reza Kolasangiani,
  • Onkar Joshi,
  • Martin A. Schwartz,
  • Tamara C. Bidone

摘要

The conformational activation of αIIbβ3integrin is crucial for platelet aggregation, a central event in hemostasis and thrombosis. Although activation can be triggered by extracellular arginine-glycine-aspartic acid (RGD)-containing ligands as well as mechanical forces, how these biochemical and mechanical cues exactly govern the structural dynamics of αIIbβ3remains unclear. Here, using all-atom molecular dynamics simulations, we show that mechanical force and RGD binding promote activation αIIbβ3through distinct mechanisms. Mechanical force applied to the RGD-binding site induces long-range, correlated motions of distant parts of the receptor, facilitating head–leg separation. In contrast, RGD binding increases localized, non-correlated fluctuations that weaken leg coordination but do not generate long-range motions. Despite these differences, both cues stabilize the open, extended conformation of αIIbβ3. Together, these findings suggest that mechanical and biochemical stimuli play complementary yet distinct roles in integrin conformational activation. A balance between global coordination and local fluctuations likely governs integrin activation in complex environments where the dominance of mechanical or biochemical cues could lead to distinct activation pathways and functional outcomes.