Oligomerisation Drives Internal Cavity Formation and Conformational Heterogeneity in Mixed Triton X-100/Tyloxapol...

Oligomeric surfactants exhibit physicochemical properties distinct from their monomeric counterparts, including lower critical micelle concentrations, yet how oligomerisation shapes the internal architecture of the micelles they form remains poorly understood. Here, we combine all-atom molecular dynamics simulations with small-angle neutron scattering (SANS) to study mixed micelles of Triton X-100 and its oligomeric analogue Tyloxapol (trimer and heptamer) across eight compositions spanning pure Triton X-100 to pure Tyloxapol. Tyloxapol content and oligomer length control the internal organization of the micelles: Tyloxapol-rich micelles adopt compact, oblate structures containing internal, water-filled cavities formed by headgroup penetration into the hydrophobic core, accompanied by reduced π-π stacking between aromatic tail groups. For pure Tyloxapol micelles, SANS corroborates the simulated size, aggregation number, oblate shape, and core hydration. Neighbor analysis shows no preferential association between Triton X-100 and Tyloxapol, consistent with random mixing across all compositions studied, while unsupervised clustering (UMAP/HDBSCAN) of Tyloxapol conformations shows that the local micelle environment selects for distinct conformational states. Together, these findings identify surfactant oligomerisation as a route to controlling internal micelle architecture, rather than only overall micelle size and shape, with implications for the design of nanocarriers and functional soft materials with tunable internal structure.