Decoding Chiral Interactions: Molecular Insights into the Selective Binding of Nanoparticles at Biological Interfaces

Chirality is a pivotal attribute of nanoparticles, crucial for biomedical applications. Despite evidence of chiral preferences in biological responses, the molecular origin of chiral selectivity remains unclear. Here, we designed gold nanoparticles (GNPs) with opposite chirality (l/d-GNPs) to unravel chiral selectivity in cell membrane attachment and protein adsorption. All-atom molecular dynamics simulations revealed that l-GNPs preferentially attach to lipid bilayers. This selectivity arises from stereomatching between chiral molecules on GNPs and lipid headgroups, leading to distinct lipid conformations and binding affinity. Anionic lipids show higher chiral preference than zwitterionic lipids due to enhanced electrostatic interactions. Chiral selectivity is diminished for lipids with primary charged groups exposed at the outermost position, as the lowest interaction energy is insensitive to stereomatching. For proteins with diverse residues, stereomatching and other interactions collectively determine chiral preference based on binding modes. Our findings provide molecular insights into chiral selectivity at nano-bio interfaces, advancing chiral nanomedicine.