Carbohydrate force fields for structure, dynamics and molecular recognition

用于结构、动力学和分子识别的碳水化合物力场

• 批准号: 9184562
• 负责人: ALEXANDER D MACKERELL
• 金额: $ 32.46万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9184562
• 关键词: Address; Antibiotics; Biological; Biological Phenomena; Biological Process; Biopolymers; Carbohydrates; Communities; Computer Simulation; Data; Development; Environment; Epitopes; Equilibrium; Eukaryota; Foundations; Glycolipids; Glycopeptides; Glycoproteins; Glycosides; Goals; HIV; HIV Envelope Protein gp120; HIV vaccine; Interstitial Cystitis; Knowledge; Laboratories; Lead; Medical; Metabolic; Methodology; Methods; Modeling; Molecular; Molecular Conformation; Nucleic Acids; Planet Earth; Polysaccharides; Prokaryotic Cells; Property; Proteins; Role; Sampling; Series; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic Agents; Tumor Suppressor Proteins; Vaccine Design; Validation; Work; aqueous; base; biological systems; carbohydrate structure; chemical function; computational chemistry; design; experimental study; field study; functional group; improved; insight; molecular dynamics; molecular recognition; neutralizing antibody; novel; novel therapeutics; public health relevance; pyranose; simulation; therapeutic development; tool; vaccine development; validation studies; web page; web site

DESCRIPTION (provided by applicant): Carbohydrates are the most abundant biopolymers on earth. Their biological functions include fuels, energy storage, metabolic intermediates, structural roles and 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. These methods will then be applied to understand the relationship of conformational properties to biological activity in the Antiproliferative Factor (APF), which may lead to the development of a therapeutic agent for the treatment of interstitial cystitis, and the N-glycans on the gp120 HIV envelope protein, which will facilitate the rational design of vaccines for HIV. These goals will be achieved by extending the additive carbohydrate force field developed in our laboratory to a wider range of chemical functionalities as well as the implementation of an automated utility to rapidly type atoms and assign parameters to the wide range of carbohydrates that include aglycone entities, such as those occurring in antibiotics. Force field development efforts will also focus on improved accuracy in the context of the optimization of the polarizable carbohydrate force field based on the classical Drude oscillator, with emphasis on furanoses, non-hydroxyl moieties common to eukaroytes and a range of glycosidic linkages, including those in glycopeptides and glycolipids. The proposed force fields will then be validated on a series of di-, tri and polysaccharides and glycoproteins, with emphasis placed on the ability of the model to reproduce aqueous solution data obtained from NMR experiments. To facilitate these validation studies we will develop and implement specific utilities for the application of Hamiltonian Replica Exchange Molecular Dynamics Simulations for improved conformational sampling of glycans, with the developed utilities made available to the computational chemistry community.

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、结构作用和分子识别。因此，碳水化合物结构-功能关系的详细知识将允许更好地理解各种生物现象，以及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提供了巨大的潜力。这项研究将扩展和改进碳水化合物研究的理论方法，包括那些参与分子识别的方法。这些方法将用于了解抗增殖因子（APF）的构象性质与生物活性的关系，这可能导致开发用于治疗间质性膀胱炎的治疗剂，以及gp 120 HIV包膜蛋白上的N-聚糖，这将导致开发用于治疗间质性膀胱炎的治疗剂。 促进艾滋病毒疫苗的合理设计。这些目标将通过将我们实验室开发的添加剂碳水化合物力场扩展到更广泛的化学功能以及实施自动化实用程序来快速类型化原子并将参数分配给包括糖苷配基实体的广泛碳水化合物来实现，例如抗生素中发生的那些。力场开发工作还将侧重于提高基于经典Drude振荡器的可极化碳水化合物力场优化的准确性，重点是呋喃糖，真核细胞常见的非羟基部分和一系列糖苷键，包括糖肽和糖脂中的糖苷键。建议的力场，然后将验证一系列的二，三和多糖和糖蛋白，重点放在该模型的能力，重现从NMR实验获得的水溶液数据。为了促进这些验证研究，我们将开发和实施具体的实用程序的应用汉密尔顿交换分子动力学模拟改进的构象采样的聚糖，与开发的实用程序提供给计算化学界。