(647a) Elucidating Thermodynamics and Mechanisms of Nanoparticle Adsorption to Lipid Bilayers Using Coarse-Grained Simulations

Engineering novel nanomaterials as biomedical agents has shown great promise, but has been limited by the lack of knowledge on interactions at the molecular scale and experimental challenges. Advances in molecular modeling techniques, such as the development of more accurate force fields and coarse-grained techniques, have enabled the accelerated exploration of large design spaces of ligand-functionalized nanoparticles to guide experimental assays and minimize resource expense. However, characterizing thermodynamic and mechanistic driving forces that modulate nanoparticle insertion into cellular membranes is still an ongoing challenge.

In this work^1,2, we have developed and parameterized coarse-grained models of ligand-coated gold nanoparticles using a bottom-up approach to study nanoparticle-bilayer interactions. These ligands have a cationic alkyl end group that we use to systematically vary lipophilicity and architecture and study their effects on nanoparticle adsorption to lipid bilayers. We employed 2D metadynamics, the string method with swarms-of-trajectories, and umbrella sampling to show that the adsorption process is more accurately described by a 2D reaction coordinate. Free energy calculations show that adsorption is nonmonotonic with respect to ligand lipophilicity and that branched alkyl end groups can reduce free energy barriers for adsorption and adsorption free energies. Mechanistic insight shows that ligand end group protrusions out of the ligand monolayer reduces free energy barriers by increasing ligand intercalation into lipid bilayers to minimize membrane disruption. However, ligand end group backfolding increases thermodynamically unfavorable lipid tail protrusions, disrupting the membrane and increasing free energy barriers. We also found that branched alkyl end groups can instead lower free energy barriers by disrupting the ligand monolayer to increase end group protrusions, increasing ligand intercalation. This also increases surface exposure of nonpolar groups to polar solvent, leading to increased nonpolar interactions with lipid tails upon adsorption and yielding more thermodynamically stable adsorbed states with lower adsorption free energies. We thus demonstrate that single-ligand descriptors, such as ligand lipophilicity, are insufficient to predict nano–bio interactions and that chain architecture also modulates nanoparticle adsorption to lipid bilayers. This work thus shows that molecular modeling can be leveraged to accelerate the design and engineering of nanomaterials, and to potentially guide experimental frameworks in biomedical applications such as targeted drug delivery and biosensing.

[1] C. A. Huang-Zhu, J. K. Sheavly, A. K. Chew, S. J. Patel, and R. C. Van Lehn. “Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers.” ACS Nano, 2024, 18 (8), 6424-6437.

[2] C. A. Huang-Zhu and R. C. Van Lehn. “Influence of branched ligand architectures on nanoparticle interactions with lipid bilayers.” Nanoscale, 2025, 17 (3), 1659-1672.