Mechanical Compressibility
of the Glycosylphosphatidylinositol
(GPI) Anchor Backbone Governed by Independent Glycosidic Linkages
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Abstract
About 1% of the human proteome is anchored to the outer
leaflet
of cell membranes via a class of glycolipids called GPI anchors. In
spite of their ubiquity, experimental information about the conformational
dynamics of these glycolipids is rather limited. Here, we use a variety
of computer simulation techniques to elucidate the conformational
flexibility of the Man-α(1→2)-Man-α(1→6)-Man-α(1→4)-GlcNAc-α-OMe
tetrasaccharide backbone <b>2</b> that is an essential and invariant
part of all GPI-anchors. In addition to the complete tetrasaccharide
structure, all disaccharide and trisaccharide subunits of the GPI
backbone have been studied as independent moieties. The extended free
energy landscape as a function of the corresponding dihedral angles
has been determined for each glycosidic linkage relevant for the conformational
preferences of the tetrasaccharide backbone (Man-α(1→2)-Man,
Man-α(1→6)Man and Man-α(1→4)-GlcNAc). We
compared the free energy landscapes obtained for the same glycosidic
linkage within different oligosaccharides. This comparison reveals
that the conformational properties of a linkage are primarily determined
by its two connecting carbohydrate moieties, just as in the corresponding
disaccharide. Furthermore, we can show that the torsions of the different
glycosidic linkages within the GPI tetrasaccharide can be considered
as statistically independent degrees of freedom. Using this insight,
we are able to map the atomistic description to an effective, reduced
model and study the response of the tetrasaccharide <b>2</b> to external forces. Even though the backbone assumes essentially
a single, extended conformation in the absence of mechanical stress,
it can be easily bent by forces of physiological magnitude