Modeling of Oligosaccharides within Glycoproteins from Free-Energy Landscapes

In
spite of the abundance of glycoproteins in biological processes,
relatively little three-dimensional structural data is available for
glycan structures. Here, we study the structure and flexibility of
the vast majority of mammalian oligosaccharides appearing in N- and
O-glycosylated proteins using a bottom up approach. We report the
conformational free-energy landscapes of all relevant glycosidic linkages
as obtained from local elevation simulations and subsequent umbrella
sampling. To the best of our knowledge, this represents the first
complete conformational library for the construction of N- and O-glycan
structures. Next, we systematically study the effect of neighboring
residues, by extensively simulating all relevant trisaccharides and
one tetrasaccharide. This allows for an unprecedented comparison of
disaccharide linkages in large oligosaccharides. With a small number
of exceptions, the conformational preferences in the larger structures
are very similar as in the disaccharides. This, finally, allows us
to suggest several efficient approaches to construct complete N- and
O-glycans on glycoproteins, as exemplified on two relevant examples.