Orientation of the saccharide chains of glycolipids at the membrane surface: Conformational analysis of the glucose-ceramide and the glucose-glyceride linkages using molecular mechanics (MM3)

Abstract

Preferred conformations of the saccharide-ceramide linkage of glucosylceramides with different ceramide structures (normal and hydroxy fatty acids) were investigated by molecular mechanics (MM3) calculations and compared with conformational features obtained for glucosylglycerolipids (diacyl and dialkyl analogues). Relaxed energy map calculations with MM3 were performed for the three bonds (C1'-O1-C1-C2, torsion angles phi, psi, and theta 1) of the glucose-ceramide/diglyceride linkage at different values of the dielectric constant. For the phi torsion of the glycosidic C1'-O1 bond the calculations show a strict preference for the +sc range whereas the psi/theta 1 energy surface is dependent on the structure of the lipid moiety as well as on the dielectric constant (epsilon). Calculations performed on glucosylceramide with normal and hydroxy fatty acids at epsilon = 4 (bilayer subsurface conditions) show three dominating conformers (psi/theta 1 = ap/-sc, -sc/ap, and ap/ap). The ap/-sc conformer, which represents the global energy minimum, is stabilized by polar interactions involving the amide group. The +sc rotamer of theta 1 is unfavored in sphingolipids due to a Hassel-Ottar effect involving the sphingosine O3 and O1 oxygen atoms. Comparative calculations on glycosylglycerolipid analogues (ester and ether derivatives) show a distinct preference for the ap rotamer of theta 1. An evaluation of the steric hindrance imposed by the surrounding membrane surface shows that in a bilayer arrangement the range of possible conformations for the saccharide-lipid linkage is considerably reduced. The significance of preferred conformations of the saccharide-ceramide linkage for the presentation and recognition of the saccharide chains of glycosphingolipids at the membrane surface is discussed.

Lipid modulation of glycolipid receptor function

“…Previous studies have shown that galactoglycerolipids, as opposed to galactosyl ceramides, are not substrates for galactose oxidase [33]. Molecular mechanics calculations of the torsional angles about the anomeric linkage in glucosyl ceramide, as opposed to glucosyl diacylglyceride [34], indicate a more extended configuration for the glycoglycerolipid which may allow tighter packing and thus restrict ligand access. Similar theoretical calculations have also predicted the restrictive influence of the plane of the membrane bilayer in glycosphingolipid recognition [35].…”

The Plasma Membrane-associated Sialidase MmNEU3 Modifies the Ganglioside Pattern of Adjacent Cells Supporting Its Involvement in Cell-to-Cell Interactions

“…The receptor role of GSLs has been hypothesized in the case of microbial infections based on their ability to interact with bacterial toxins and microbial lectins (6,7). Conformational analysis confirms that the orientation of the oligosaccharide chains of glycolipids at the cell surface complies with the possibility to interact with extracellular molecules (8,9). Indeed, synthetic analogues of GSL oligosaccharides are able to block cell-cell recognition (10).…”

A Major Fraction of Glycosphingolipids in Model and Cellular Cholesterol-containing Membranes Is Undetectable by Their Binding Proteins

“…GSL carbohydrate conformation (10,94) is also restricted by the plane of the membrane (11). Membrane curvature may alter the plane of the membrane bilayer relative to the GSL carbohydrate (29,61) to affect ligand binding.…”