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1. Binding, unbinding and aggregation of crescent-shaped nanoparticles on nanoscale tubular membranes

   https://doi.org/10.1039/D0SM01642J  

   Spangler, Eric J.; Olinger, Alexander D.; Kumar, P. B.; Laradji, Mohamed (January 2021, Soft Matter)

   null (Ed.)

   Using molecular dynamics simulations of a coarse-grained implicit solvent model, we investigate the binding of crescent-shaped nanoparticles (NPs) on tubular lipid membranes. The NPs adhere to the membrane through their concave side. We found that the binding/unbinding transition is first-order, with the threshold binding energy being higher than the unbinding threshold, and the energy barrier between the bound and unbound states at the transition that increases with increasing the NP's arclength L np or curvature mismatch μ = R c / R np , where R c and R np are the radii of curvature of the tubular membrane and the NP, respectively. Furthermore, we found that the threshold binding energy increases with increasing either L np or μ . NPs with curvature larger than that of the tubule ( μ > 1) lie perpendicularly to the tubule's axis. However, for μ smaller than a specific arclength-dependent mismatch μ *, the NPs are tilted with respect to the tubule's axis, with the tilt angle that increases with decreasing μ . We also investigated the self-assembly of the NPs on the tubule at relatively weak adhesion strength and found that for μ > 1 and high values of L np , the NPs self-assemble into linear chains, and lie side-by-side. For μ < μ * and high L np , the NPs also self-assemble into chains, while being tilted with respect to the tubule's axis. 

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2. Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers

   https://doi.org/10.1021/acsnano.3c11854  

   Huang-Zhu, Carlos A.; Sheavly, Jonathan K.; Chew, Alex K.; Patel, Samarthaben J.; Van Lehn, Reid C. (February 2024, ACS Nano)

   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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3. Effective repulsive interaction between Janus polymer-grafted nanoparticles adhering to lipid vesicles

   https://doi.org/10.1063/5.0249522  

   Darling, Jordan F; Sharma, Abash; Zhu, Yu; Spangler, Eric J; Laradji, Mohamed (January 2025, The Journal of Chemical Physics)

   The adhesion of nanoparticles to lipid vesicles causes curvature deformations to the membrane to an extent determined by the competition between the adhesive interaction and the membrane’s elasticity. These deformations can extend over length scales larger than the size of a nanoparticle, leading to an effective membrane-curvature-mediated interaction between nanoparticles. Nanoparticles with uniform surfaces tend to aggregate into unidimensionally close-packed clusters at moderate adhesion strengths and endocytose at high adhesion strengths. Here, we show that the suppression of close-packed clustering and endocytosis can be achieved by the surface modification of the nanoparticles into Janus particles where a moiety of their surface is grafted with polymers under a good solvent condition. The osmotic pressure of the polymer brushes prevents membrane wrapping of the nanoparticles’ moieties that are grafted with polymers, thus suppressing their endocytosis. Furthermore, a repulsion between polymer brushes belonging to two nearby nanoparticles destabilizes the dimerization of the nanoparticles over a wide range of values of the polymers’ molecular weight and grafting density. This surface modification of nanoparticles should allow for reliable, non-close-packed, and tunable self-assemblies of nanoparticles. 

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4. Penetration and preferential binding of charged nanoparticles to mixed lipid monolayers: interplay of lipid packing and charge density

   https://doi.org/10.1039/d0sm01945c  

   Chaudhury, Anurag; Debnath, Koushik; Bu, Wei; Jana, Nikhil R.; Basu, Jaydeep Kumar (February 2021, Soft Matter)

   null (Ed.)

   Designing of nanoparticles (NPs) for biomedical applications or mitigating their cytotoxic effects requires microscopic understanding of their interactions with cell membranes. Such insight is best obtained by studying model biomembranes which, however, need to replicate actual cell membranes, especially their compositional heterogeneity and charge. In this work we have investigated the role of lipid charge density and packing of phase separated Langmuir monolayers in the penetration and phase specificity of charged quantum dot (QD) binding. Using an ordered and anionic charged lipid in combination with uncharged but variable stiffness lipids we demonstrate how the subtle interplay of zwitterionic lipid packing and anionic lipid charge density can affect cationic nanoparticle penetration and phase specific binding. Under identical subphase pH, the membrane with higher anionic charge density displays higher NP penetration. We also observe coalescence of charged lipid rafts floating amidst a more fluidic zwitterionic lipid matrix due to the phase specificity of QD binding. Our results suggest effective strategies which can be used to design NPs for diverse biomedical applications as well as to devise remedial actions against their harmful cytotoxic effects especially against respiratory diseases. 

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5. Lipophilicity of Cationic Ligands Promotes Irreversible Adsorption of Nanoparticles to Lipid Bilayers

   https://doi.org/10.1021/acsnano.0c09732  

   Lochbaum, Christian A.; Chew, Alex K.; Zhang, Xianzhi; Rotello, Vincent; Van Lehn, Reid C.; Pedersen, Joel A. (January 2021, ACS Nano)

   null (Ed.)

   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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