Glycoprotein Modeling System for Internal Coordinate Mechanics

描述(由申请人提供)：我们建议开发几个基本组件，使糖蛋白能够在ICM中全面建模：ECEPP05力场的碳水化合物扩展，常见糖基化部分的库，在蛋白质结构上构建糖的工具，以及对其随机动力学和对接到糖结合蛋白的模拟。这些组件将共同组成糖基化建模系统。蛋白质上的碳水化合物部分(多糖)在一系列生理过程中发挥着重要作用，包括病毒逃避免疫系统、血液抗凝、癌症进展、细胞-细胞识别以及蛋白质的正确折叠和加工。在三维结构水平上对其功能的认识一直落后于常规多肽。多糖的柔韧性、无序性和异质性给实验结构的确定带来了困难。分子力学技术越来越多地允许在原子水平上对基本的生物过程进行电子模拟。Molsoft的ICM(内部坐标力学)软件平台是一个特别有效的建模工具，因为它在描述分子结构时使用了内部变量，而不是传统的笛卡尔坐标。这项拟议的发展将允许将这种方法应用于碳水化合物的建模。为结构生物学家配备ICM中的糖蛋白建模系统，将有助于将多糖的分子模拟和结构预测提高到更高的准确度。成功的结构建模最终将有助于提高我们对疾病潜在分子机制的理解，并有助于加快基于结构的药物发现工作。 与公共健康相关：蛋白质(多糖)上的碳水化合物部分在一系列生理过程中发挥重要作用，包括病毒逃避免疫系统、血液抗凝、癌症进展、细胞-细胞识别以及蛋白质的正确折叠和加工。为结构生物学家配备ICM中的糖蛋白建模系统，将有助于将多糖的分子模拟和结构预测提高到更高的准确度。成功的结构建模最终将有助于提高我们对疾病潜在分子机制的理解，并有助于加快基于结构的药物发现工作。

DESCRIPTION (provided by applicant): We propose to develop several essential components that would allow comprehensive modeling of glycoproteins in ICM: a carbohydrate extension of the ECEPP05 force-field, a library of common glycosylating moieties, tools for glycan construction on protein structures, and simulations of their stochastic dynamics and docking to glycan-binding proteins. Together these components will comprise the Glycosylation Modeling System. Carbohydrate moieties on the proteins (glycans) play an essential role in a range of physiological processes, including viral evasion from the immune system, blood anticoagulation, the progression of cancer, cell-cell recognition, and the correct folding and processing of proteins. Understanding of their function on the level of three-dimensional structure has been lagging behind that of the regular polypeptides. Flexibility, disorder and heterogeneity of glycans make experimental structure determination difficult. Molecular mechanics techniques increasingly allow in-silico simulation of essential biological processes at the atomic level. Molsoft's ICM (Internal Coordinate Mechanics) software platform is a particularly efficient modeling tool because of its use of internal variables, rather than traditional Cartesian coordinates, in the description of the molecular structure. This proposed development will allow to apply this approach to modeling of carbohydrates. Equipping structural biologists with the Glycoprotein Modeling System in ICM will help bring molecular simulations and structure predictions for glycans to the next level of accuracy. Successful structure modeling will ultimately help improve our understanding of molecular mechanisms underlying disease and help to accelerate structure-based drug discovery efforts. PUBLIC HEALTH RELEVANCE: Carbohydrate moieties on the proteins (glycans) play an essential role in a range of physiological processes, including viral evasion from the immune system, blood anticoagulation, the progression of cancer, cell-cell recognition, and the correct folding and processing of proteins. Equipping structural biologists with the Glycoprotein Modeling System in ICM will help bring molecular simulations and structure predictions for glycans to the next level of accuracy. Successful structure modeling will ultimately help improve our understanding of molecular mechanisms underlying disease and help accelerate structure-based drug discovery efforts.