Gangliosides are
important glycosphingolipids involved
in a multitude
of physiological functions. From a physicochemical standpoint, this
is related to their ability to self-organize into nanoscopic domains,
even at molar concentrations of one per 1000 lipid molecules. Despite
recent experimental and theoretical efforts suggesting that a hydrogen
bonding network is crucial for nanodomain stability, the specific
ganglioside moiety decisive for the development of these nanodomains
has not yet been identified. Here, we combine an experimental technique
achieving nanometer resolution (Förster resonance energy transfer
analyzed by Monte Carlo simulations) with atomistic molecular dynamic
simulations to demonstrate that the sialic acid (Sia) residue(s) at
the oligosaccharide headgroup dominates the hydrogen bonding network
between gangliosides, driving the formation of nanodomains even in
the absence of cholesterol or sphingomyelin. Consequently, the clustering
pattern of asialoGM1, a Sia-depleted glycosphingolipid
bearing three glyco moieties, is more similar to that of structurally
distant sphingomyelin than that of the closely related gangliosides
GM1and GD1awith one and two Sia groups, respectively.