The hydrophobicity of monolayer-protected gold nanoparticles is a crucial design parameter that influences self-assembly, preferential binding to proteins and membranes, and other nano-bio interactions. Predicting the effects of monolayer components on nanoparticle hydrophobicity is challenging due to the nonadditive, cooperative perturbations to interfacial water structure that dictate hydrophobicity at the nanoscale. In this work, we quantify nanoparticle hydrophobicity by using atomistic molecular dynamics simulations to calculate local hydration free energies at the nanoparticle-water interface. The simulations reveal that the hydrophobicity of large gold nanoparticles is determined primarily by ligand end group chemistry, as expected. However, for small gold nanoparticles, long alkanethiol ligands interact to form anisotropic bundles that lead to substantial spatial variations in hydrophobicity even for homogeneous monolayer compositions. We further show that nanoparticle hydrophobicity is modulated by changing the ligand structure, ligand chemistry, and gold core size, emphasizing that single-ligand properties alone are insufficient to characterize hydrophobicity. Finally, we illustrate that hydration free energy measurements correlate with the preferential binding of propane as a representative hydrophobic probe molecule. Together, these results show that both physical and chemical properties influence the hydrophobicity of small nanoparticles and must be considered together when predicting gold nanoparticle interactions with biomolecules.
Keywords: classical molecular dynamics simulations; gold nanoparticles; hydrophobicity; indirect umbrella sampling; self-assembled monolayers; water density fluctuations.