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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (03))
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Wehrle, Janna P
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University of Maryland Baltimore
Schools of Pharmacy
United States
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Yang, Mingjun; Aytenfisu, Asaminew H; MacKerell Jr, Alexander D (2018) Proper balance of solvent-solute and solute-solute interactions in the treatment of the diffusion of glucose using the Drude polarizable force field. Carbohydr Res 457:41-50
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Lin, Fang-Yu; MacKerell Jr, Alexander D (2018) Improved Modeling of Halogenated Ligand-Protein Interactions Using the Drude Polarizable and CHARMM Additive Empirical Force Fields. J Chem Inf Model :
Lin, Fang-Yu; MacKerell Jr, Alexander D (2018) Polarizable Empirical Force Field for Halogen-Containing Compounds Based on the Classical Drude Oscillator. J Chem Theory Comput 14:1083-1098
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