Molecular mechanisms of integrin αvβ8 activation regulated by graphene, boron nitride and black phosphorus nanosheets

Integrin αvβ8 is a heterodimeric transmembrane protein on macrophages. Nanosheets can activate the integrin and elicit immune responses, exhibiting adverse immunotoxicity. Understanding the mechanism of integrin activation regulated by nanosheets is crucial for safe and effective use of nanosheets in biomedical applications. Herein, we performed all-atom molecular dynamics simulations to clarify the interactions between integrin αvβ8 in the cell membrane and three types of nanosheets, graphene (GRA), hexagonal boron nitride (BN), and black phosphorus (BP). We observed that BP could adsorb the intracellular end of αv monomer and thus break the inner membrane clasp, an important hydrophobic cluster for maintaining the inactive state of integrin. The association between αv and β8 subunit is weakened, promoting the integrin activation. By contrast, GRA and BN exert little influence on the association state of the integrin. Interestingly, the puckered structure of BP affects the integrin activation, where BP with the armchair direction perpendicular to the membrane plane cannot unpack the integrin. Moreover, the perturbation effect of nanosheets on the membrane was also evaluated. BP shows a milder effect on membrane structures and lipid properties than GRA and BN. This work unravels the molecular basis on the activation of integrin mediated by three nanosheets, and suggests the toxicity and therapeutic effect of well-established nanomaterials in the immune system.