Influence of Molecular Shape and Hydrogen Bonding on Glycolipid Self-assembly into Thermotropic Gyroid Phases

Abstract

Periodic network morphologies such as the double gyroid (DG) are promising for a wide range of applications, from optical materials and organic semiconductors to separation membranes and drug delivery vehicles. While natural glycolipids are a constituent of cell membranes, synthetic glycolipids have emerged as candidates for producing thermotropic DG phases with sub-5 nm domains. Despite this potential, difficulties in producing stereochemically-pure glycolipids and a lack of known design rules governing DG self-assembly limit their broad use. Our recent work identified two key factors stabilizing DG in ten anomerically pure Guerbet cellobiosides: a bent molecular topology and moderate hydrogen bonding between sugar headgroups. However, the influence of glycolipid shape vs. hydrogen bonding could not be decoupled, as these factors depend on both headgroup and anomeric stereochemistry. To disentangle these effects, we synthesized 20 anomerically-pure Guerbet glycolipids with different disaccharide headgroups (lactose, maltose) and Guerbet tails (C₈-C₂₄) and compared them with ten similar cellobiosides. Analysis of the thermotropic phase behavior using differential scanning calorimetry, polarized optical microscopy, small-angle X-ray scattering, and complementary molecular simulations identified numerous cases of DG phase formations, with phase stability dependent on headgroup type and anomeric stereochemistry. With respect to molecular shape, high stability DG phases were promoted by molecules with kinks in topology at similar positions; the most stable DG phases also shared similar inter-molecular hydrogen bonding motifs between specific headgroup hydroxyls. Beyond revealing design guidelines for producing DG phases, this comprehensive understanding of glycolipid self-assembly may accelerate development of biomimetic materials, as the liquid crystalline behavior of natural glycolipids plays a pivotal role in biological functions.