Mechanical Compressibility of the Glycosylphosphatidylinositol (GPI) Anchor Backbone Governed by Independent Glycosidic Linkages

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• 作者：Marko Wehle ; Ivan Vilotijevic ; Reinhard Lipowsky ; Peter H. Seeberger ; Daniel Varon Silva ; Mark Santer
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：November 21, 2012
• 年：2012
• 卷：134
• 期：46
• 页码：18964-18972
• 全文大小：524K
• 年卷期：v.134,no.46(November 21, 2012)
• ISSN：1520-5126

文摘

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-伪(1鈫?)-Man-伪(1鈫?)-Man-伪(1鈫?)-GlcNAc-伪-OMe tetrasaccharide backbone 2 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-伪(1鈫?)-Man, Man-伪(1鈫?)Man and Man-伪(1鈫?)-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 2 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.