Influence of branched ligand architectures on nanoparticle interactions with lipid bilayers

Gold nanoparticles functionalized with organic cationic ligands have shown promise as biomedical agents, but their interactions with cellular membranes are not yet well-understood and design rules for ligands that promote desired cellular interactions are lacking. Past experimental studies have demonstrated that ligand lipophilicity, quantified by the ligand end group partition coefficient, can be used as a descriptor for predicting nano-bio interactions, but such a descriptor is incapable accounting for ligand architecture, such as chain branching. To probe the effects of ligand end group architecture on ligand-lipid interactions, we perform molecular dynamics simulations to investigate how ligand alkyl chain branching modulates the thermodynamics and mechanisms of nanoparticle adsorption to lipid membranes. We designed four pairs of 2 nm diameter gold nanoparticles where each pair had ligand end groups with similar lipophilicity but varying alkyl chain architecture (<i>e.g.</i>, one long alkyl chain <i>vs.</i> two short chains) to isolate branching effects from lipophilicity. Free energy calculations and mechanistic insight revealed that alkyl end group branching can decrease free energy barriers for adsorption by disrupting ligand monolayer packing, increasing end group protrusions that lead to favorable ligand intercalation with minimal membrane disruption. Furthermore, increased end group branching promotes adsorption by increasing the exposure of nonpolar surface area to water, which results in a greater reduction of free energy upon exposure to the nonpolar core of the lipid bilayer. These results show that ligand chain architecture can modulate nano-bio interactions, limiting the exclusive use of lipophilicity as a descriptor to predict cellular uptake of surface-functionalized nanoparticles.