Interfacial Solute Organization Governs Mixed-Osmolyte Compatibility under Salt Stress

Mixed osmolytes protect charged biomolecular and nanomaterial interfaces under salt stress, but their combined effects are often nonadditive. Here we identify interfacial solute organization as a molecular criterion that determines whether a mixture is protective or antagonistic via combining computer simulations and experiments. All-atom simulations of negatively charged α-quartz nanoslabs, supported by SHINERS and ATR-FTIRS experiments on silica surfaces, show that urea weakens glycine-mediated protection but strengthens TMAO- and betaine-mediated protection. The difference arises from nanoscale organization: urea associates with glycine at the charged interface, suppressing glycine-driven cation displacement and reducing intersurface repulsion, whereas urea remains spatially independent of TMAO and betaine, allowing their ion-modulating effects to combine constructively. The same directional behavior is reproduced in Aβ(1–40) dimerization simulations and Aβ-derived AcKE aggregation kinetic experiments. These results establish interfacial solute organization as a transferable rule for designing multicomponent protective environments.