Optimizing the Crowding Strategy: Sugar-Based Ionic Micelles in the Dilute-to-Condensed Regime

Abstract

In the present study, we explore the effect of concentration on micelles made by different gangliosides, which are ionic biological glycolipids bearing multisugar headgroups with huge steric hindrance. Moreover, strong preferential interactions exist among like-conformer headgroups that can keep the ganglioside micelles in a trapped configuration. We extend the well-known ionic-amphiphiles paradigm, where local condensation and micelle crowding are matched by forming larger aggregates at increasing concentration. In fact, we force the balance between interparticle and intraparticle interactions while allowing for like conformers to modulate rebalancing. In the vast experimental framework, obtained by Small Angle X-ray scattering (SAXS) experiments, a theoretical model, accounting for a collective conformational transition of the bulky headgroups, is developed and successfully tested. It allows us to shed some light on the nature and coupling of the intermolecular forces involved in the interactions among glycolipid micelles. Energy minimization leads to complex behavior of the aggregation number on increasing concentration, fully consistent with the experimental landscape. From a biological perspective, this result could be reflected in the properties of ganglioside-enriched rafts on cell membranes, with a nonlinear structural response to approaching bodies such as charged proteins.

The Glycosphingolipid GM3 Modulates Conformational Dynamics of the Glucagon Receptor

“…We recognize that one area for future research will be the effects of lipid headgroup charge states and possible interactions with counterions on the interactions of lipids with the GCGR and related proteins. There have been a number of studies of the likely importance of such effects for PIP 2 ( 76 , 77 ); for gangliosides, the situation is less clear, although a number of studies (e.g., ( 78 , 79 )) suggest interactions with counterions would merit further investigation, especially in the context of likely self-association of gangliosides in membranes ( 68 , 80 ). In addition to understanding better the physicochemical properties of more complex mixtures of lipids, it will be important to integrate these with ongoing advances in lipidome-based models of the cell membrane environment ( 32 ).…”

“…We recognize that one area for future research will be the effects of lipid headgroup charge states and possible interactions with counterions on the interactions of lipids with the GCGR and related proteins. There have been a number of studies of the likely importance of such effects for PIP 2 (76,77); for gangliosides, the situation is less clear, although a number of studies (e.g., (78,79)) suggest interactions with EC IC GCGR GM3 FIGURE 7 GM3 binding to GCGR promotes ECD opening. Schematic overview of the effect of GM3 (orange) on the behavior of GCGR (light blue) when devoid of peptide ligands.…”