Dynamics of ganglioside headgroup in lipid environment: Molecular dynamics simulations of GM1 embedded in dodecylphosphocholine micelle

Recognition of membrane-anchored glycosphingolipid receptors by various ligands is the key event in several biological phenomena. However, mere presence of these cell-surface receptors does not always ensure their recognition and binding by their respective ligands, a phenomenon termed "crypticity". Earlier studies have suggested that different glycan headgroup, orientations exposing and/or masking different epitopes may explain the crypticity of glycolipids. The effect of lipid environment on the orientation and conformation of GM1 ganglioside has been investigated in the present study by MD simulation technique in an attempt to understand the structural basis of crypticity. In addition, the effect of the length of the ceramide hydrocarbon tails on the headgroup conformation has also been investigated. MD simulations for 1 ns were performed with explicit water molecules for both GM 1 headgroup (GM 1-Os) and GM1 embedded in dodecylphosphocholine micelle. The simulations show that the conformations of the hydrocarbon tails, ceramide-saccharide linkages, and the headgroup are inter-related and are affected by micellar packing considerations. The conformations of GalNAc-beta1 -->4-Gal and Neu5Ac-alpha2 -->3-Gal linkages were found to be restricted when GM I is embedded in the micelle compared to that in GM1-Os. The GalNAc-beta1 -->4-Gal linkage being a branch point, affects the orientation/accessibility of all the residues linked to GalNAc. If such a disallowed glycan conformation is necessary for recognition by, and binding to, their ligands, then the glycans may become cryptic. The ceramide with 8-carbon hydrocarbon tails was found to adopt a "surface-bound" configuration. In contrast, ceramide with 12- or 16-carbon tails was found to adopt "micelle-inserted" configuration. The effect of lipid environment was found to be the least on the oligosaccharide linked to the ceramide with hexadecyl tails. Thus, the headgroup conformation in this case is essentially the same as that of the free headgroup. This probably explains the lesser crypticity of glycolipids with longer hydrocarbon tails