Atomic-resolution conformational analysis of the GM3 ganglioside in a lipid bilayer and its implications for ganglioside-protein recognition at membrane surfaces.

Eukaryotic cells depend on external surface markers, such as gangliosides, to recognize and bind various other molecules as part of normal growth and maturation. The localization of gangliosides in the outer leaflet of the plasma membrane, also make them targets for pathogens trying to invade the host cells. Since ganglioside-mediated interactions are critical to both beneficial and pathological processes, much effort has been directed at determining the 3D structures of their carbohydrate head groups; however, technical difficulties have generally prevented the characterization of the head group in intact membrane-bound gangliosides. Determining the 3D structure and presentation of gangliosides at the surface of membranes is important in understanding how cells interact with their local environment. Here, we employ all-atom explicit solvent molecular dynamics (MD) simulations, using the GLYCAM06 force field, to model the conformation and dynamics of ganglioside G(M3) (alpha-Neu5Ac-(2-3)-beta-Gal-(1-4)-beta-Glc-ceramide) in a DMPC lipid bilayer. By comparison with MD simulations of the carbohydrate head-group fragment of G(M3) alone, it was possible to quantify and characterize the extent of changes in head-group presentation and dynamics associated with membrane anchoring. The accuracy of data from the MD simulations was determined by comparison to NMR and crystallographic data for the head group in solution and for G(M3) in membrane-mimicking environments. The experimentally consistent model of G(M3), in a lipid bilayer, was then used to model the recognition of G(M3) at the cell surface by known protein receptors.