Cholesterol mediates the potential adverse influence of graphene quantum dots on placental lipid membrane model

Nanomaterial-biomembrane interactions constitute a critical biological process in assessing the toxicity of such materials in theoretical studies. However, many investigations simplify these interactions by using membrane models containing only one or a few lipid types, deviating significantly from the complexity of real membrane compositions. In particular, cholesterol, a ubiquitous lipid essential for regulating membrane fluidity and closely linked to various diseases, is often overlooked. Consequently, the role of cholesterol in nanomaterial-biomembrane interactions remains poorly understood. In this study, we employ molecular dynamics (MD) simulations to explore the effect of graphene quantum dots (GQDs) on a realistic placental lipid membrane model, aiming to elucidate the role of cholesterol in these interactions. Our MD results reveal that both GQD monomers and clusters can spontaneously insert into the placental lipid membrane model, driven by strong van der Waals interaction energy. Further analyses indicate that cholesterol and POPC lipids primarily contribute to interfacial interactions. Notably, cholesterol can be squeezed into the bilayer interface, forming a unique structure where it is sandwiched between the GQD cluster and the membrane's bottom leaflet. More significantly, cholesterol, together with the GQD cluster, exhibits free lateral movement, suggesting a strong affinity of cholesterol for GQD clusters. These findings highlight the critical role of cholesterol in mediating GQD insertion into the biomembrane. Structural analyses of the membrane further demonstrate deformation of the placental lipid membrane model during GQD penetration. Finally, free energy calculations confirm that the insertion of both GQD monomers and clusters into the placental lipid membrane model is energetically favorable. Overall, this study not only sheds new light on the potential harmful effects of GQDs on realistic placental membranes but also provides the first theoretical evidence of the pivotal role of cholesterol in nanomaterial-biomembrane interactions, contributing to a deeper understanding of nanomaterial-cell membrane interactions.