Atomic-resolution conformational analysis of the GM3 ganglioside in a lipid bilayer and its implications for ganglioside-protein recognition at membrane surfaces
Atomic-resolution conformational analysis of the GM3 ganglioside in a lipid bilayer and its implications for ganglioside-protein recognition at membrane surfaces
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DOI：
10.1093/glycob/cwn137
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发表时间：
2009-04-01
期刊：
影响因子：
4.3
通讯作者：
Woods, Robert J.
中科院分区：
文献类型：
--
作者：
DeMarco, Mari L.;Woods, Robert J.
真核细胞依赖于外部表面标志物，如神经节苷脂，识别和结合各种其他分子作为正常生长和成熟的一部分。神经节苷脂在质膜外叶的定位也使它们成为试图入侵宿主细胞的病原体的靶点。由于神经节苷脂介导的相互作用是至关重要的有益的和病理过程中，许多努力已被定向在确定其碳水化合物头基的3D结构，然而，技术上的困难，一般阻止在完整的膜结合的神经节苷脂的头基的表征。确定膜表面神经节苷脂的3D结构和呈现对于理解细胞如何与其局部环境相互作用非常重要。在这里，我们采用全原子显式溶剂分子动力学（MD）模拟，使用GLYCAM 06力场，模拟DMPC脂质双层中神经节苷脂G（M3）（α-Neu 5Ac-（2-3）-β-Gal-（1-4）-β-Glc-神经酰胺）的构象和动力学。通过与单独的G（M3）的碳水化合物头基片段的MD模拟比较，可以量化和表征与膜锚定相关的头基呈现和动力学变化的程度。通过与溶液中的头基和膜模拟环境中的G（M3）的NMR和晶体学数据进行比较，确定MD模拟数据的准确性。实验一致的模型G（M3），在脂质双层，然后被用来模拟G（M3）在细胞表面的识别已知的蛋白质受体。
Eukaryotic cells depend on external surface markers, such as gangliosides, to recognize and bind various other molecules as part of normal growth and maturation. The localization of gangliosides in the outer leaflet of the plasma membrane, also make them targets for pathogens trying to invade the host cells. Since ganglioside-mediated interactions are critical to both beneficial and pathological processes, much effort has been directed at determining the 3D structures of their carbohydrate head groups; however, technical difficulties have generally prevented the characterization of the head group in intact membrane-bound gangliosides. Determining the 3D structure and presentation of gangliosides at the surface of membranes is important in understanding how cells interact with their local environment. Here, we employ all-atom explicit solvent molecular dynamics (MD) simulations, using the GLYCAM06 force field, to model the conformation and dynamics of ganglioside G(M3) (alpha-Neu5Ac-(2-3)-beta-Gal-(1-4)-beta-Glc-ceramide) in a DMPC lipid bilayer. By comparison with MD simulations of the carbohydrate head-group fragment of G(M3) alone, it was possible to quantify and characterize the extent of changes in head-group presentation and dynamics associated with membrane anchoring. The accuracy of data from the MD simulations was determined by comparison to NMR and crystallographic data for the head group in solution and for G(M3) in membrane-mimicking environments. The experimentally consistent model of G(M3), in a lipid bilayer, was then used to model the recognition of G(M3) at the cell surface by known protein receptors.