Functionalization of nanoparticles with specific ligands is helpful to control specific diagnostic and therapeutic responses such as protein adsorption, cell targeting, and circulation. Precision delivery critically depends on a fundamental understanding of the interplay between surface chemistry, ligand dynamics, and interaction with the biochemical environment. Due to limited atomic-scale insights into the structure and dynamics of nanoparticle-bound ligands from experiments, relationships of grafting density and ligand chemistry to observable properties such as hydrophilicity and protein interactions remain largely unknown. In this work, we uncover how self-assembled monolayers (SAMs) composed of multisegment ligands such as thioalkyl-PEG-(N-alkyl)amides on gold nanoparticles can mimic mixed hydrophobic and hydrophilic ligand coatings, including control of patterns, hydrophilicity, and specific recognition properties. Our results are derived from molecular dynamics simulations with the INTERFACE-CHARMM36 force field at picometer resolution and comparisons to experiments. Small changes in ligand hydrophobicity, via adjusting the length of the N-terminal alkyl groups, tune water penetration by multiples and control superficial ordering of alkyl chains from 0 to 70% regularity. Further parameters include the grafting density of the ligands, curvature of the nanoparticle surfaces, type of solvent, and overall ligand length, which were examined in detail. We explain the thermodynamic origin of the formation of heterogeneous patterns of multisegment ligand SAMs and illustrate how different degrees of ligand order on the nanoparticle surface affect interactions with bovine serum albumin. The resulting design principles can be applied to a variety of ligand chemistries to customize the behavior of functionalized nanoparticles in biological media and enhance therapeutic efficiency.
Keywords: ligand patterns; molecular dynamics simulation; multisegment ligands; nanoparticle solubility; nanoparticles; protein recognition; self-assembled monolayers.