Selective inhibition of platelet inflammatory tether formation via force-modulated vibrational states of integrin...

Platelet inflammatory tether (PITT) formation under pathological shear is a central driver of thrombo-inflammation and bleeding complications in severe infections, yet current antiplatelet therapies lack selectivity because they target equilibrium integrin affinity rather than force-dependent adhesion dynamics. The mechanistic origin of catch-bond stabilization in integrin αIIbβ3 under inflammatory shear, and its separation from physiological hemostatic adhesion, therefore remains unresolved.

Here, we develop a quantum-informed mechanochemical model that explicitly links shear-induced mechanical loading to the vibrational energy landscape of the metal-ion-dependent adhesion site (MIDAS) of integrin αIIbβ3. Within a Born-Oppenheimer-reduced framework, the MIDAS coordination mode is represented as a force-deformed anharmonic potential, enabling analytic determination of force-dependent vibrational eigenstates, transition-state barriers, and dissociation kinetics. These quantum-derived descriptors are systematically mapped onto stochastic escape and mechanokinetic formalisms to predict bond lifetimes under shear. The model demonstrates that catch-bond behavior emerges from force-induced spectral compression and curvature softening of the MIDAS energy landscape, producing a finite mechanochemical window in which bond lifetime is maximized. We further identify a separation between a kinetic critical force governing lifetime optimization and a higher spectral critical force associated with structural destabilization. This separation provides a physical basis for selectively suppressing PITT formation through modulation of force-sensitive transition-state energetics while preserving low-force hemostatic adhesion. Our results establish energy-landscape engineering as a first-principles strategy for force-selective antiplatelet intervention and a general theoretical framework for mechanosensitive biological adhesion.