Ganglioside-Lipid and Ganglioside-Protein InteractionsRevealed by Coarse-Grained and Atomistic Molecular Dynamics Simulations

摘要

Gangliosides are glycolipids in which an oligosaccharide headgroup containing one or more sialic acids is connected to a ceramide. Gangliosides reside in the outer leaflet of the plasma membrane and play a crucial role in various physiological processes such as cell signal transduction and neuronal differentiation by modulating structures and functions of membrane proteins. Because the detailed behavior of gangliosides and protein-ganglioside interactions are poorly known, we investigated the interactions between the gangliosides GM1 and GM3 and the proteins aquaporin (AQP1) and WALP23 using equilibrium molecular dynamics simulations and potential of mean force calculations at both coarse-grained (CG) and atomistic levels. In atomistic simulations, on the basis of the GROMOS force field, ganglioside aggregation appears to be a result of the balance between hydrogen bond interactions and steric hindrance of the headgroups. GM3 clusters are slightly larger and more ordered than GM1 clusters due to the smaller headgroup of GM3. The different structures of GM1 and GM3 clusters from atomistic simulations arenot observed at the CG level based on the Martini model, implyinga difference in driving forces for ganglioside interactions in atomisticand CG simulations. For protein-ganglioside interactions, in the atomisticsimulations, GM1 lipids bind to specific sites on the AQP1 surface,whereas they are depleted from WALP23. In the CG simulations, theganglioside binding sites on the AQP1 surface are similar, but gangliosideaggregation and protein-ganglioside interactions are more prevalentthan in the atomistic simulations. Using the polarizable Martini watermodel, results were closer to the atomistic simulations. Althoughexperimental data for validation is lacking, we proposed modifiedMartini parameters for gangliosides to more closely mimic the sizesand structures of ganglioside clusters observed at the atomistic level.