Predicting the Physicochemical Properties and Biological Activities of Monolayer-Protected Gold Nanoparticles Using Simulation-Derived Descriptors.

Gold nanoparticles are versatile materials for biological applications because their properties can be modulated by assembling ligands on their surface to form monolayers. However, the physicochemical properties and behaviors of monolayer-protected nanoparticles in biological environments are difficult to anticipate because they emerge from the interplay of ligand-ligand and ligand-solvent interactions that cannot be readily inferred from ligand chemical structure alone. In this work, we demonstrate that quantitative nanostructure-activity relationship (QNAR) models can employ descriptors calculated from molecular dynamics simulations to predict nanoparticle properties and cellular uptake. We performed atomistic molecular dynamics simulations of 154 monolayer-protected gold nanoparticles and calculated a small library of simulation-derived descriptors that capture nanoparticle structural and chemical properties in aqueous solution. We then parametrized QNAR models using interpretable regression algorithms to predict experimental measurements of nanoparticle octanol-water partition coefficients, zeta potentials, and cellular uptake obtained from a curated database. These models reveal that simulation-derived descriptors can accurately predict experimental trends and provide physical insight into what descriptors are most important for obtaining desired nanoparticle properties or behaviors in biological environments. Finally, we demonstrate model generalizability by predicting cell uptake trends for 12 nanoparticles not included in the original data set. These results demonstrate that QNAR models parametrized with simulation-derived descriptors are accurate, generalizable computational tools that could be used to guide the design of monolayer-protected gold nanoparticles for biological applications without laborious trial-and-error experimentation.