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

我们一直在用分子动力学模拟方法研究碳水化合物在溶液中的确定。为了得到溶液中构象变化的精细能量，我们将伞形取样方法应用到CHARMM程序中。得到了新碳二糖在水中构象势能平均力的Ramachandran自由能图。势能图显示了与先前在真空中计算的该分子的行为不同的行为。这种方法也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由于糖链被认为具有多种生物学功能而引起了人们的极大关注。然而，糖链的作用细节还没有完全弄清楚。已知免疫球蛋白G(Ig G)形成抗原-抗体复合体，并进一步与Ig G Fc部分的受体(FCR)结合。Nose和Wigzell com…More对有或没有碳水化合物链的抗体进行了比较，结果表明，缺乏碳水化合物的抗体将导致抗体不能与巨噬细胞上的FCR相互作用。Kato进行了核磁共振实验，表明在有或没有糖链的条件下，Fc部分呈现不同的构象。为了更准确地研究糖链的作用，对免疫球蛋白Fc部分进行了分子动力学模拟。根据Harris等人的晶体结构，构建了Ig G Fc部分的结构。艾尔。通过移除Fab片段。虽然显式水分子的计算对于适当处理水溶液中的生物聚合物是至关重要的，但在这种情况下这样的计算太昂贵了。因此，我们首先尝试用模拟溶剂效应的SIMPLE方法进行分子动力学模拟，如高介电常数和广义Born方法。作为这项工作的基本信息，我们计算了构建Ig G寡糖的双糖的Ramachandran势表面图，并进一步研究了糖-糖和糖-蛋白质复合体中存在的基本相互作用，如CH-p相互作用。用从头算方法研究了吡喃葡萄糖环的环间转化反应。结果表明，E_3构象是环相互转化的过渡态。内禀反应坐标(IRC)计算表明，E_3构象是从^4C_1到B_3，o通过E_3构象的环相互转化路径的过渡态。较少

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