▎ 摘　　要

Despite the remarkable electrochemical properties of graphene, strong van der Waals attraction between graphene and biomolecules often causes cytotoxicity, which hinders its applications in the biomedical field. Unfortunately, surface passivation of graphene might stimulate undesired immune response as the nanomaterial triggers cytokine production through membrane receptor activation. Herein, we use all-atom Molecular Dynamics (MD) simulations to unravel the underlying mechanism of graphene-induced inside-out activation of integrin alpha(v)beta(8), a prominent membrane receptor expressed in immune cells. We model the transmembrane (TM) domains of integrin alpha(v)beta(8) in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer and observe the structural changes in the integrin-membrane complex when interacting with a graphene nanosheet across the membrane. We find that the beta(8) TM domain interacts with the graphene nanosheet directly or indirectly through extracted lipids, facilitating the pulling of a beta(8) subunit away from an alpha(v) subunit and thus leading to the disruption of the TM domain association by breaking the hydrophobic cluster in the cytoplasmic domains of the alpha(v) and beta(8) subunits. Alanine substitution of two conserved phenylalanine residues on the alpha(v) subunit at this hydrophobic cluster further reveals the importance of a stable T-shaped structure in retaining integrin in its inactive state. Our results agree with previous studies on the interactions between other integrin subtypes and their endogenous activators, suggesting an intriguing role that the graphene nanosheet may play in the integrin-related signal transduction during its interaction with the membrane.