Small Molecule Stabilization of Proteins and Nanoparticles: Rethinking Colloidal Stabilization

Amino acids have long been used in biological and pharmaceutical formulations, but their stabilizing effects are often described only for particular proteins. This talk examines a broader mechanism: small molecules modify colloidal interactions in proteins, DNA and synthetic nanoparticles. Measurements of osmotic virial coefficients and potentials of mean force reveal consistent effects across these systems. A model of weakly interacting amino acids binding to patchy colloidal surfaces predicts experimentally measured dissociation constants; proline–lysozyme predictions and measurements agree within a factor of two. Experiments also test predictions that short peptides outperform the same number of free amino acids and that charged amino acids stabilize oppositely charged proteins. The consequences extend to suppression of liquid–liquid phase separation and cellular stress granules, and doubled insulin bioavailability in mice when co-formulated with proline. The results motivate treating amino acids as active regulators of colloidal behavior alongside familiar influences such as salt.