Hydrophilicity and topology interplay determines positioning of guest molecules in lipid cubic phases

Lipid nanostructures with inverse bicontinuous cubic symmetries are of paramount importance as delivery structures of active compounds in the pharmaceutical, cosmetic and food science fields. By atomistic molecular dynamics, here we study the internalization of three molecules of varying hydrophilicity, fructose, caffeine and vitamin D, within a cubic phase with primitive symmetry, allowing us to assess how the incorporation of the guest molecule is affected by the interplay between its hydrophilicity and the topology of the host membrane. For lipophilic molecules our results reveal the details of molecular localization and orientation, which allow estimating the bending modulus of the membrane by means of a phenomenological model based on the physics of liquid crystals. For more hydrophilic molecules, we show that the unique topological and geometrical features of bicontinuous cubic phases (BCPs) lead to non-trivial effects on the lipid-water interface, primarily controlled by their curvature, resulting in an enthalpically driven distancing of the guest molecule from the interface. In particular, we detect a preference of hydrophilic molecules to migrate towards the flat points of the lipid-water interface, from which we may infer a preferred onset of nucleation in phase separation processes, such as in membrane-protein crystallization.