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

## TL;DR

This study uses simulations to show how biochemical and mechanical signals activate a platelet receptor through different structural pathways.

## Contribution

The paper reveals distinct structural mechanisms by which mechanical forces and RGD ligands activate αIIbβ3 integrin.

## Key findings

- Mechanical force induces long-range motions in αIIbβ3, promoting head-leg separation.
- RGD binding increases localized fluctuations without causing long-range motions.
- Both mechanical and biochemical cues stabilize the open conformation of αIIbβ3.

## Abstract

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.

The online version contains supplementary material available at 10.1007/s00018-026-06138-9.