(169p) Ligand Lipophilicity and Architecture Influence Mechanisms and Thermodynamics of Nanoparticle Adsorption to Lipid Bilayers

The design of ligand-coated nanoparticles that can translocate across biological membranes with minimal membrane disruption has been challenging due to the lack of knowledge on cell-penetrating mechanisms. Ligand lipophilicity has been studied as the primary descriptor for predicting biological interactions for this class of nanoparticles, particularly in drug discovery. However, the molecular mechanisms and thermodynamic driving forces through which these ligands interact with biological membranes are yet to be fully explained through experiments. Furthermore, the timescales of experimental synthesis and characterization have posed challenges by limiting the design space for these nanomaterials as biomedical agents.

In this work¹, we employ coarse-grained molecular dynamics simulations to study the adsorption of ligand-coated gold nanoparticles to single-component bilayers. The ligands studied possess a cationic linear alkyl end group that varies in lipophilicity through alkyl chain length. We used path variables and the string method with swarms-of-trajectories to define the minimum free energy path for adsorption as a function of two collective variables. We define the distance along this path as a reaction coordinate and compute a corresponding potential of mean force using umbrella sampling for each nanoparticle. We show that adsorption to a simple bilayer is favorable for all nanoparticles, but a non-monotonic trend in free energy barrier for adsorption is present as a function of linear alkyl end group length (and thus lipophilicity). End groups with low or high lipophilicity initiate adsorption through unfavorable lipid tail protrusions, whereas end groups of intermediate lipophilicity protrude favorably out of the ligand monolayer to intercalate into the lipid bilayer. We also show that ligand end group architecture (i.e., number of end group branches) modulates the thermodynamics of adsorption. Ligand end groups of similar lipophilicity will exhibit lower free energy barriers as their degree of branching increases. We thus demonstrate that ligand lipophilicity and end group architecture are both important descriptors for nanoparticle adsorption to single-component bilayers. This work details a computational framework to study nanoparticle-membrane interactions that can be leveraged as a design space exploration tool for nanomaterials, and can potentially guide experimental frameworks in biomedical applications, such as 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.