Carbohydrate force fields for structure, dynamics and molecular recognition

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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.