CONFORMATIONAL AND PROTEIN BINDING ANALYSIS OF OLIGOSACCHARIDES

低聚糖的构象和蛋白质结合分析

• 批准号: 3752042
• 负责人: P K QASBA
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3752042
• 关键词: N acetylglucosamine; carbohydrate receptor; carbohydrate structure; chemical binding; computer simulation; galactose; glycosyltransferase; lectin; ligands; molecular dynamics; molecular energy level; molecular site; monosaccharides; oligosaccharides; receptor binding; solutions

Diverse oligosaccharide structures that are generated with the help of specific glycosyltransferases from a relatively small number of saccharide units, have an enormous potential for encoding information. This information content for a given oligosaccharide is increased furthermore by the existence of several conformers which exist in equilibrium in solution that have been implicated in several biological functions. Most of the experimental studies in solution give a time averaged conformation, closely resembling the global energy minimum conformer, that however, need not be the bioactive conformer. To have a precise idea about the bioactive conformer, it is essential to have the information about all the conformers which are accessible by this particular oligosaccharide. We have applied molecular dynamics technique to study all the possible conformations of some bi- and triantennary oligosaccharides that are the ligands of glycosyltransferases and of asialoglycoprotein cell surface receptor (ASGP-R). Most of the earlier studies on the conformational behavior of oligosaccharides were limited to the study of individual di- and trisaccharide fragments which constitute the actual oligosaccharides present on glycoproteins. Molecular dynamics simulation of the molecules for one nano second by considering all the monosaccharides simultaneously has provided a wealth of information about the conformational preferences of these molecules. The results show that contrary to earlier beliefs oligosaccharides show considerable amount of flexibility. The relative distance and orientation of the galactose residues on the 1,2- and 1,4- branches of the 1,3-arm of triantennary oligosaccharide are invariant during most of the simulation period. Contrary to the 1,3 arm, the 1,6 arm is close to the GlcNAc residues of the core oligosaccharide structure. Binding of the 1,3-arm may bring about a conformational change in the 1,6- arm and lead to its interaction with a lectin, e.g ASGP-R, providing additional binding energy.

不同的低聚糖结构是由 从相对较少的糖类中提取的特异性糖基转移酶 单元，具有编码信息的巨大潜力。这 给定寡糖的信息含量进一步增加 由于存在着几个平衡存在的构象 已经牵涉到几种生物功能的溶液。多数 在溶液中的实验研究中给出了时间平均构象， 非常类似于全球能量最小构象，然而，需要 而不是生物活性的构象。要想准确地了解 生物活性构象，重要的是要有关于所有 这种特定的低聚糖可以接触到的构象。我们 已经应用分子动力学技术研究了所有可能的 一些双天线和三天线低聚糖的构象 糖基转移酶和去唾液酸糖蛋白细胞表面的配体 受体(ASGP-R)。早期的研究大多是关于构象的 低聚糖的行为仅限于对单个双糖的研究。 和组成实际低聚糖的三糖片段 存在于糖蛋白上。分子的分子动力学模拟 同时考虑所有单糖的时间为一纳秒 提供了大量关于构象偏好的信息。 这些分子中。结果表明，与早先的看法相反 低聚糖表现出相当大的灵活性。相对的 1，2-和1，4-半乳糖残基的距离和取向 三天线低聚糖的1，3-臂的分支是不变的 在模拟期间的大部分时间内。与1，3臂相反，1，6 ARM是接近GlcNAc残基的核心寡糖结构。 1，3-臂的结合可能会导致1，6-环的构象变化。 臂并导致其与凝集素相互作用，例如ASGP-R，提供 附加结合能。