Monolayer-Protected Anionic Au Nanoparticles Walk into Lipid Membranes Step by Step

The design of ligand-protected metal nanoparticles (NPs) with biomedical applications relies on the understanding, at the molecular level, of their interactions with cell membranes. Here we study, via unbiased coarse grained molecular dynamics simulations, the kinetics and the thermodynamics of the interaction between anionic ligand-protected gold NPs and model lipid membranes. The NP-membrane interaction is a three-step process: electrostatics-driven adhesion to the membrane surface, hydrophobic contact and final embedding in the membrane core via anchoring of the charged ligands to both membrane leaflets. Our free energy calculations show that anchoring is highly favorable and not reversible. Furthermore, we show that the interaction pathway of NPs with random surface arrangement of anionic and hydrophobic ligands is characterized by two metastable configurations: adsorbed at the membrane surface, and membrane-embedded. Patched ligand arrangements, instead, lead to the stabilization of a third, intermediate metastable configuration, resulting in a much slower kinetics of interaction with the membrane.