Max Planck Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
J Am Chem Soc. 2012 Nov 21;134(46):18964-72. doi: 10.1021/ja302803r. Epub 2012 Nov 13.
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 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-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 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.
人类蛋白质组大约有 1%通过一类称为糖基磷脂酰肌醇（GPI）锚的糖脂锚定在细胞膜的外小叶。尽管它们无处不在，但关于这些糖脂构象动力学的实验信息相当有限。在这里，我们使用各种计算机模拟技术来阐明所有 GPI 锚的必需且不变部分的 Man-α(1→2)-Man-α(1→6)-Man-α(1→4)-GlcNAc-α-OMe 四糖主链 2 的构象灵活性。除了完整的四糖结构外，还研究了 GPI 主链的所有二糖和三糖亚基作为独立的部分。已经确定了作为四糖主链构象偏好相关的每个糖苷键的相应二面角的扩展自由能景观。我们比较了在不同寡糖中相同糖苷键获得的自由能景观。这种比较表明，一个键的构象性质主要由其两个连接的碳水化合物部分决定，就像在相应的二糖中一样。此外，我们可以证明 GPI 四糖中不同糖苷键的扭转可以被视为统计上独立的自由度。利用这一见解，我们能够将原子描述映射到有效、简化的模型，并研究四糖 2 对外部力的响应。尽管在没有机械应力的情况下，主链基本上呈现出单一的扩展构象，但它可以很容易地被生理幅度的力弯曲。
