Shaping up for structural glycomics: a predictive protocol for oligosaccharide conformational analysis applied to N-linked glycans.
Shaping up for structural glycomics: a predictive protocol for oligosaccharide conformational analysis applied to N-linked glycans.
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DOI：
10.1016/j.carres.2013.10.011
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发表时间：
2014-01-13
影响因子：
3.1
通讯作者：
Almond, Andrew
中科院分区：
文献类型：
--
作者：
Sattelle, Benedict M.;Almond, Andrew
验证了N-连接甘露糖核心和唾液酸化刘易斯（sLe）触角的水性10 μs模拟。序列依赖性糖苷键和吡喃糖环μs运动与生物活性有关。sLea和sLex中的堆叠吡喃糖在μs时间尺度上是刚性的。在sLex的25 μs模拟中，所有已知的构象异构体都在最初的10 μs动态内采样。提出无偏10 μs模拟作为系统和准确的糖组学3D分析的途径。人类糖组包括一个巨大的未开发的3D结构信息库，它是聚糖识别的关键，也是合理设计的模拟化学探针、药物和生物材料的新时代。为了在热力学平衡下对寡糖构象群和交换率进行常规预测，我们应用硬件加速的水分子动力学来模拟N-聚糖中的μs运动，这些运动是炎症和免疫的基础。在10 μs的模拟中，甘露糖核心、唾液酸刘易斯（sLe）触角和组成子序列的构象平衡与之前的改进（X射线和核磁共振）一致。糖苷键和吡喃糖环弯曲的分支，连接位置，和二级结构的影响，暗示序列依赖性运动的糖功能多样性。预测通过实验和常规（ns）模拟难以精确定量的连接和环构象转变发生在μs时间尺度上。所有的环填充非椅子形状和堆叠的半乳糖和岩藻糖吡喃sLea和sLex被硬化，这表明一个可利用的3D签名的细胞粘附蛋白结合。超过25 μs的sLex动力学分析表明，只有10 μs足以探索所有的水相构象。这种模拟协议，它产生的构象是独立的初始三维结构的合奏，提出作为一种途径来理解寡糖识别和结构-活性关系，对发展的碳水化合物为基础的新的化学实体。
Aqueous 10 μs simulations of N-linked mannosyl cores and sialyl Lewis (sLe) antennae are validated. Sequence dependent glycosidic linkage and pyranose ring μs motions are implicated in bioactivity. Stacked pyranoses in sLea and sLex are predicted to be atypically rigid on μs timescales. In a 25 μs simulation of sLex, all known conformers were sampled within the initial 10 μs of dynamics. Unbiased 10 μs simulations are proposed as a route to systematic and accurate glycomic 3D-analysis. The human glycome comprises a vast untapped repository of 3D-structural information that holds the key to glycan recognition and a new era of rationally designed mimetic chemical probes, drugs, and biomaterials. Toward routine prediction of oligosaccharide conformational populations and exchange rates at thermodynamic equilibrium, we apply hardware-accelerated aqueous molecular dynamics to model μs motions in N-glycans that underpin inflammation and immunity. In 10 μs simulations, conformational equilibria of mannosyl cores, sialyl Lewis (sLe) antennae, and constituent sub-sequences agreed with prior refinements (X-ray and NMR). Glycosidic linkage and pyranose ring flexing were affected by branching, linkage position, and secondary structure, implicating sequence dependent motions in glycomic functional diversity. Linkage and ring conformational transitions that have eluded precise quantification by experiment and conventional (ns) simulations were predicted to occur on μs timescales. All rings populated non-chair shapes and the stacked galactose and fucose pyranoses of sLea and sLex were rigidified, suggesting an exploitable 3D-signature of cell adhesion protein binding. Analyses of sLex dynamics over 25 μs revealed that only 10 μs were sufficient to explore all aqueous conformers. This simulation protocol, which yields conformational ensembles that are independent of initial 3D-structure, is proposed as a route to understanding oligosaccharide recognition and structure–activity relationships, toward development of carbohydrate-based novel chemical entities.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
2.1
作者：
HAASNOOT, CAG;DELEEUW, FAAM;ALTONA, C
通讯作者：
ALTONA, C
影响因子：
3.1
作者：
DOWD, MK;FRENCH, AD;REILLY, PJ
通讯作者：
REILLY, PJ
DOI：
10.1016/0005-2795(80)90174-9
发表时间：
1980-01-01
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA
影响因子：
--
作者：
JARDETZKY, O
通讯作者：
JARDETZKY, O
影响因子：
15
作者：
ICHIKAWA, Y;LIN, YC;WONG, CH
通讯作者：
WONG, CH