Carbohydrate Force Field for 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、结构作用和重要的分子识别，包括在疫苗、细胞-细胞识别和细菌毒素的致病活性中的作用。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。为了探索这些结构-功能关系，理论方法提供了巨大的潜力。本研究将提高我们对碳水化合物结构性质的认识，以及理论方法在碳水化合物研究中的应用，特别是涉及分子识别的理论方法。这些目标将首先通过量子力学（QM）计算来研究对单糖和双糖的构象性质很重要的间扭式和异构效应。来自QM计算的信息将为碳水化合物的经验力场的发展奠定基础，该力场与CHARMM力场兼容于蛋白质、脂质和核酸，从而允许在异质系统中对碳水化合物进行计算研究，包括糖蛋白和糖脂。优化后的力场参数将通过分子动力学（MD）模拟研究进行验证，该研究对具有生物学意义的含碳水化合物系统进行了实验数据验证。在完成拟议的研究后，将更好地了解碳水化合物的结构特性，包括单糖、多糖和非均相系统中的碳水化合物，包括疫苗和细菌毒素。此外，一个新的碳水化合物的经验力场将提供给科学界。碳水化合物力场的可用性与蛋白质、脂质和核酸的可用力场兼容，将大大提高计算方法对这些生物基本分子的适用性，促进治疗剂、疫苗和反恐剂的合理设计。

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, including roles in vaccines, cell-cell recognition and the pathogenic activity of bacterial toxins. Accordingly, detailed knowledge of carbohydrate structure-function relationships would allow for better understanding of a variety of biological phenomena. To explore these structure-function relationships, theoretical approaches offer great potential. The proposed study will enhance both our understanding of the structural properties of carbohydrates, as well as the utility of theoretical methods in studying carbohydrates, especially those involved in molecular recognition. These goals will be achieved by first investigating the gauche and anomeric effects, known to be important for the conformational properties of mono- and disaccharides, via quantum mechanical (QM) calculations. Information from the QM calculations will lay the groundwork for the development of an empirical force field for carbohydrates that is compatible with CHARMM force fields for proteins, lipids and nucleic acids, thereby allowing for computational studies of carbohydrates in heterogeneous systems, including glycoproteins and glycolipids. The optimized force field parameters will be validated via molecular dynamics (MD) simulation studies of biologically interesting carbohydrate-containing systems for which experimental data are available. Upon completion of the proposed study, a better understanding of the structural properties of carbohydrates ranging from monosaccharides, polysaccharides and carbohydrates in heterogeneous systems, including vaccines and bacterial toxins, will be obtained. In addition, a new empirical force field for carbohydrates will be made available to the scientific community. The availability of a carbohydrate force field that is compatible with available force fields for proteins, lipids and nucleic acids will greatly enhance the applicability of computational approaches to these biologically essential molecules, facilitating the rational design of therapeutic agents, vaccines and counterterrorism agents.