In Search of a Structural Pattern in Crazy Sugarsidentification of Conformation Clusters of the Oligosaccharides Within Glycoproteins with LEUS

Abstract

Oligosaccharides within glycoproteins, also called glycans, have been recognized to have critical biological roles: in regulation of the immune system, cellular growth, cell-cell adhesion, infection, inflammation and malignant transformations. Their structural diversity has enabled them to have this broad range of functionalities. Glycans can be built from monomers that differ in size, linkage types, linkage positions and charges. Furthermore, there is a lack of reliable 3D structural information from experimental techniques because of their flexible nature. To tackle this problem, we used enhanced molecular dynamics simulation techniques to offer 3D models in the absence of experimental structural data. With this aim, ‘motion libraries’ of all disaccharides constituting the most common glycans were constructed using an enhanced sampling method, local elevation umbrella sampling (LEUS). In the build-up phase, biased potentials were constructed for the glycosidic linkages of disaccharides, which were subsequently used to sample the conformational space for larger oligosaccharides. First, the effect of consecutive linkages on the disaccharide free-energy landscape was assessed at the trisaccharide level. Next, some of the most common human glycans, such as complex and high-mannose N-glycans, were modelled. In addition to these glycans, the effect of core-fucosylation is investigated on these models. The disaccharide motion libraries are used to sample the conformation space of these oligosaccharide units along the glycosidic dihedral angle. Several clustering schemes are used to identify different structural patterns observed in the different glycan types. Here, we show preliminary results for solution structure clusters of the most common glycans found in human glycoproteins.