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Development of the Free energy Calculation method and the Construction of Carbohydrate Structure Library

自由能计算方法的发展和碳水化合物结构库的构建

基本信息

批准号：
17300093
负责人：
UEDA Kazuyoshi
金额：
$ 9.8万
依托单位：
Yokohama National University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17300093/
关键词：
Molecular dynamics Bioinformatics Free energy Carbohydrate

项目摘要

We have been investigating the confirmation of the carbohydrates in solution by using molecular dynamics simulation. In order to obtain the fine energy of the conformational change in solution, we applied the umbrella sampling method to charmm program. We obtained the Ramachandran free energy map of the conformational potential mean force for neocarrabiose in water. The potential energy map showed the different behavior compared with that of calculated in a previous study for this molecule in vacuum. This method was tried to apply to other carbohydrates in solution, such as oligosaccharide in immunoglogrin G.Carbohydrates in glycoprotein attract a great deal of attention because the glycan chains are suggested to play a variety of biological functions. However, the details of the role of glycan chains have not fully understood yet. Immunoglobulin G (IgG) is known to form antigen-antibody complex and it further bind to the receptors (FcR) for the Fc portion of IgG.. Nose and Wigzell com … More pared the IgG antibodies with or without carbohydrate chains and showed that the carbohydrate-deficient IgG will lead to an inability of the antibodies to interact with FcR on macrophages. Kato performed NMR experiment and suggested that the Fc portion takes different conformation between the conditions with or without glycan chains. In order to investigate the role of glycan chain more precisely, molecular dynamics simulation of the Fc portion of IgG was performed. The structure of the Fc portion of IgG was constructed from the crystal structure of Harris, et. Al. by removing the Fab fragments. Although the calculation with explicit water molecules is crucial in a proper treatment of biopolymers in aqueous solution, such calculation is too expensive in this case. Therefore, we first tried to perform the molecular dynamics simulation by using simple method, which mimic the solvent effect, such as high dielectric constant and generalized Born method. As a basic information for this work, we calculated the ramachandran potential surface map for disaccharides which constructs the IgG oligosaccharide.We further studied the basic interaction exists in the carbohydrate-carbohydrate and carbohydrate-protein complexes, such as CH-p interaction. Ring interconversion of the glucopyranose ring was also investigated by using ab initio calculation. The results showed that the E_3 conformation was found to be a transition state of the ring interconversion. Intrinsic reaction coordinate (IRC) calculations indicated that the E_3 conformation is a transition state of the ring interconversion path from ^4C_1 to B_3,o via E_3 conformation. Less

我们一直在用分子动力学模拟的方法研究溶液中碳水化合物的确定。为了得到溶液中构象变化的精细能量，我们在charmm程序中应用了伞式采样方法。我们得到了新糖在水中的构象势平均力的Ramachandran自由能图。势能图显示了该分子在真空中的不同行为，与先前的研究结果相比较。该方法被尝试应用于溶液中的其他碳水化合物，如免疫球蛋白g中的低聚糖。糖蛋白中的碳水化合物因其聚糖链被认为具有多种生物学功能而受到广泛关注。然而，关于聚糖链作用的细节还没有完全了解。已知免疫球蛋白G （IgG）可形成抗原抗体复合物，并进一步与IgG Fc部分的受体（FcR）结合。Nose和Wigzell等…More对含有或不含碳水化合物链的IgG抗体进行了比较，结果表明缺乏碳水化合物的IgG抗体将导致抗体无法与巨噬细胞上的FcR相互作用。Kato进行了核磁共振实验，发现在有或没有聚糖链的条件下，Fc部分呈现不同的构象。为了更精确地研究聚糖链的作用，我们对IgG的Fc部分进行了分子动力学模拟。IgG的Fc部分的结构是基于Harris等人的晶体结构，通过去除Fab片段构建的。虽然明确水分子的计算对于水溶液中生物聚合物的适当处理至关重要，但这种计算在这种情况下过于昂贵。因此，我们首先尝试用模拟溶剂效应的简单方法，如高介电常数和广义玻恩法进行分子动力学模拟。作为本工作的基础资料，我们计算了构建IgG低聚糖的双糖的ramachandran电位表面图。我们进一步研究了碳水化合物-碳水化合物和碳水化合物-蛋白质复合物中存在的基本相互作用，如CH-p相互作用。用从头算法研究了葡萄糖醛酸环的环间转换。结果表明，E_3构象是环相互转化的过渡态。本征反应坐标（IRC）计算表明，E_3构象是由^4C_1到B_3的环相互转化路径的过渡态，通过E_3构象。少