Carbohydrate force fields for structure, dynamics and molecular recognition

描述（由申请人提供）：碳水化合物是地球上最丰富的生物聚合物。它们的生物学功能包括燃料、能量储存、代谢中间体、结构作用以及重要的分子识别。因此，对碳水化合物结构-功能关系的详细了解将有助于更好地理解各种生物现象，并促进治疗剂和能源技术的发展。探索这种结构-功能关系的理论方法具有很大的潜力。本研究将扩展和改进碳水化合物研究的理论方法，包括涉及分子识别的理论方法，并提高我们对这些重要分子的结构和动力学性质的理解，包括溶剂化对这些性质的作用。这些目标将通过将我们实验室在初始资助期间开发的添加剂经验力场扩展到含有双糖的呋喃糖、糖蛋白和糖脂，以及包括非羟基官能团的碳水化合物来实现。力场开发工作还将启动基于经典Drude振荡器的极化力场优化，并包括5点极化水模型的开发。提出的力场将在一系列二、三和多糖、糖蛋白和糖脂上进行验证。针对目标分子的各种实验数据是可用的，所提出的计算也将产生对这些生物重要系统特性的见解。在完成拟议的研究后，经过验证的碳水化合物的加性和极化力场将提供给科学界，这些力场与蛋白质、脂质和核酸的可用力场兼容。这些工具的可用性将大大提高计算方法对这些生物基本分子的适用性，促进新型治疗剂、疫苗、清洁能源方法和反恐剂的开发。

DESCRIPTION (provided by applicant): Carbohydrates are the most abundant biopolymers on earth. Their biological functions include fuels, energy storage, metabolic intermediates, structural roles and, importantly, molecular recognition. Accordingly, detailed knowledge of carbohydrate structure-function relationships will allow for better understanding of a variety of biological phenomena as well as facilitate the development of therapeutic agents and energy technologies. To explore such structure-function relationships theoretical approaches offer great potential. The proposed study will expand and improve theoretical methods for the study of carbohydrates, including those involved in molecular recognition, and improve our understanding of the structural and dynamical properties of these important molecules, including the role of solvation on those properties. These goals will be achieved by extending the additive empirical force field developed in our laboratory during the initial funding period to furanose containing disaccharides, glycoproteins and glycolipids, and carbohydrates that include non-hydroxyl functional groups. Force fields developments efforts will also initiate the optimization of a polarizable force field based on the classical Drude oscillator and include development of a 5-point polarizable water model. The proposed force fields will then be validated on a series of di-, tri and polysaccharides, glycoproteins and glycolipids. A variety of experimental data is available for the targeted molecules and the proposed calculations will also yield insights into the properties of these biologically important systems. Upon completion of the proposed study validated additive and polarizable force fields for carbohydrates will be available to the scientific community that are compatible with available force fields for proteins, lipids and nucleic acids. The availability of these tools will greatly enhance the applicability of computational approaches to these biologically essential molecules, facilitating the development of novel therapeutic agents, vaccines, approaches to clean energy and counterterrorism agents. PUBLIC HEALTH RELEVANCE: Carbohydrate's biological functions include fuels, energy storage, metabolic intermediates, structural roles and molecular recognition. The proposed study will develop new computational models for carbohydrates that will allow for studies on the structural and dynamical properties at a molecular level of detail. These tools will facilitate the development of novel therapeutic agents, vaccines, approaches to clean energy and counterterrorism agents.