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，以便在ICM中对糖蛋白进行全面建模：ECEPP05力场的碳水化合物扩展，常见糖基化片段库，在蛋白质结构上构建聚糖的工具，以及它们的随机动力学模拟和与聚糖结合蛋白的对接。这些组件将共同构成糖基化建模系统。蛋白质上的碳水化合物部分（聚糖）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，癌症的进展，细胞-细胞识别以及蛋白质的正确折叠和加工。对它们在三维结构水平上的功能的了解一直落后于对常规多肽的了解。多糖的柔韧性、无序性和非均质性使实验结构测定变得困难。分子力学技术越来越允许在原子水平上进行基本生物过程的硅模拟。Molsoft的ICM（内部坐标力学）软件平台是一种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。这一建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聚糖的分子模拟和结构预测提高到更高的精度。成功的结构建模最终将有助于提高我们对潜在疾病的分子机制的理解，并有助于加速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.