Atomistic Insights into Graphene Oxide Dot Interactions with Integrin αVβ3 from Microsecond Simulations

Graphene oxide (GO)-based nanomaterials functionalized with targeting ligands are promising platforms for selective cancer drug delivery. Among relevant targets, integrin αVβ3 is a highly overexpressed receptor in several solid tumors and is commonly targeted using cyclic Arg-Gly-Asp (cRGD) peptides. However, the molecular details governing the interaction between cRGD-functionalized GO dots and integrins remain poorly understood. In this work, all-atom molecular dynamics simulations are employed to investigate the interaction between integrin αVβ3 and a nanocarrier composed of a GO dot coated with polyethylene glycol (PEG) and functionalized with cRGD ligands. Multiple 1 μs simulation replicas are used to characterize both specific ligand recognition and non-specific nanocarrier/receptor interactions. The simulations show that cRGD binding within the integrin-binding pocket is stable, indicating that the nanocarrier does not impair receptor recognition. Beyond cRGD-mediated binding, both PEG-cRGD chains and GO itself establish additional contacts with the protein, whose nature and distribution are modulated by the relative orientation of the GO plane. Overall, the structural dynamics of integrin αVβ3 remains preserved upon nanocarrier binding. These findings provide atomistic insights into the interplay between ligand-mediated and multivalent surface-mediated interactions of GO-based nanocarriers with integrins for the rational design of selective nanocarriers for cancer therapy.