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The interactions of ligand-functionalized nanoparticles with the cell membrane affect cellular uptake, cytotoxicity, and related behaviors, but relating these interactions to ligand properties remains challenging. In this work, we perform coarse-grained molecular dynamics simulations to study how the adsorption of ligand-functionalized cationic gold nanoparticles (NPs) to a single-component lipid bilayer (as a model cell membrane) is influenced by ligand end group lipophilicity. A set of 2-nm diameter NPs, each coated with a monolayer of organic ligands that differ only in their end groups, was simulated to mimic NPs recently studied experimentally. Metadynamics calculations were performed to determine key features of the free energy landscape for adsorption as a function of the distance of the NP from the bilayer and the number of NP-lipid contacts. These simulations revealed that NP adsorption is thermodynamically favorable for all NPs due to the extraction of lipids from the bilayer and into the NP monolayer. To resolve ligand-dependent differences in adsorption behavior, string method calculations were performed to compute minimum free energy pathways for adsorption. These calculations revealed a surprising non-monotonic dependence of the free energy barrier for adsorption on ligand end group lipophilicity. Large free energy barriers are predicted for the least lipophilic end groups because favorable NP-lipid contacts are initiated only through the unfavorable protrusion of lipid tail groups out of the bilayer. The smallest free energy barriers are predicted for end groups of intermediate lipophilicity which promote NP-lipid contacts by intercalating within the bilayer. Unexpectedly, large free energy barriers are also predicted for the most lipophilic end groups which remain sequestered within the ligand monolayer rather than intercalating within the bilayer. These trends are broadly in agreement with past experimental measurements and reveal how subtle variations in ligand lipophilicity dictate adsorption mechanisms and associated kinetics by influencing the interplay of lipid-ligand interactions.
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Lipophilicity of Cationic Ligands Promotes Irreversible Adsorption of Nanoparticles to Lipid Bilayers
A mechanistic understanding of the influence of the surface properties of engineered nanomaterials on their interactions with cells is essential for designing materials for applications such as bioimaging and drug delivery as well as for assessing nanomaterial safety. Ligand-coated gold nanoparticles have been widely investigated because their highly tunable surface properties enable investigations into the effect of ligand functionalization on interactions with biological systems. Lipophilic ligands have been linked to adverse biological outcomes through membrane disruption, but the relationship between ligand lipophilicity and membrane interactions is not well understood. Here, we use a library of cationic ligands coated on 2 nm gold nanoparticles to probe the impact of ligand end group lipophilicity on interactions with supported phosphatidylcholine lipid bilayers as a model for cytoplasmic membranes. Nanoparticle adsorption to and desorption from the model membranes were investigated by quartz crystal microbalance with dissipation monitoring. We find that nanoparticle adsorption to model membranes increases with ligand lipophilicity. The effects of ligand structure on gold nanoparticle attachment were further analyzed using atomistic molecular dynamics simulations, which showed that the increase in ligand lipophilicity promotes ligand intercalation into the lipid bilayer. Together, the experimental and simulation results could be described by a two-state model that accounts for the initial attachment and subsequent conversion to a quasi-irreversibly bound state. We find that only nanoparticles coated with the most lipophilic ligands in our nanoparticle library undergo conversion to the quasi-irreversible state. We propose that the initial attachment is governed by interaction between the ligands and phospholipid tail groups, whereas conversion into the quasi-irreversibly bound state reflects ligand intercalation between phospholipid tail groups and eventual lipid extraction from the bilayer. The systematic variation of ligand lipophilicity enabled us to demonstrate that the lipophilicity of cationic ligands correlates with nanoparticle-bilayer adsorption and suggested that changing the nonpolar ligand R group promotes a mechanism of ligand intercalation into the bilayer associated with irreversible adsorption.
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- Award ID(s):
- 2001611
- PAR ID:
- 10220892
- Date Published:
- Journal Name:
- ACS Nano
- ISSN:
- 1936-0851
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1021/acsnano.0c09732
