Carbohydrate force fields for structure, dynamics and molecular recognition

描述(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，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。为了探索这种结构-功能关系，理论方法提供了巨大的潜力。这项拟议的研究将扩展和改进碳水化合物研究的理论方法，包括那些涉及分子识别的方法。然后，这些方法将被应用于了解抗增殖因子(APF)的构象性质与生物活性的关系，这可能导致开发治疗间质性膀胱炎的治疗剂，以及gp120 HIV包膜蛋白上的N-糖链，这将 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碳水化合物力场扩展到更广泛的化学功能以及实施自动实用程序来实现，以快速键入原子并为包括苷元实体在内的广泛碳水化合物分配参数，例如那些出现在抗生素中的碳水化合物。力场开发工作还将侧重于在优化基于经典Drude振子的可极化碳水化合物力场的背景下提高准确性，重点是呋喃类化合物、真核生物常见的非羟基部分以及一系列糖苷键，包括糖肽和糖脂中的那些。然后，将在一系列二、三和多糖和糖蛋白上验证所提出的力场，重点是该模型再现从核磁共振实验中获得的水溶液数据的能力。为了促进这些验证研究，我们将开发和实施特定的实用程序，用于应用哈密顿复制交换分子动力学模拟来改进多糖的构象采样，并将开发的实用程序提供给计算化学社区。

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.