All-atom simulations reveal distinct pathways for α_IIbβ₃ activation by biochemical vs. mechanical cues

The conformational activation of α_IIbβ₃integrin 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_IIbβ₃remains unclear. Here, using all-atom molecular dynamics simulations, we show that mechanical force and RGD binding promote activation α_IIbβ₃through 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_IIbβ₃. 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.