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.

Public Health Relevance

Carbohydrate's biological functions include fuels, energy storage, metabolic intermediates, structural roles and molecular recognition. The proposed study will develop improved computational models for carbohydrates that will allow for studies on the structural and dynamical properties at a molecular level of detail. These tools will be used to facilitate development of novel therapeutic agents for the treatment of interstitial cystitis an for the development of vaccines against HIV.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Wehrle, Janna P
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University of Maryland Baltimore
Schools of Pharmacy
United States
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Lakkaraju, Sirish Kaushik; Lemkul, Justin A; Huang, Jing et al. (2016) DIRECT-ID: An automated method to identify and quantify conformational variations--application to β2 -adrenergic GPCR. J Comput Chem 37:416-25
Lee, Jumin; Cheng, Xi; Swails, Jason M et al. (2016) CHARMM-GUI Input Generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM Simulations Using the CHARMM36 Additive Force Field. J Chem Theory Comput 12:405-13
Lemkul, Justin A; Huang, Jing; Roux, Benoît et al. (2016) An Empirical Polarizable Force Field Based on the Classical Drude Oscillator Model: Development History and Recent Applications. Chem Rev 116:4983-5013
Cavalier, Michael C; Ansari, Mohd Imran; Pierce, Adam D et al. (2016) Small Molecule Inhibitors of Ca(2+)-S100B Reveal Two Protein Conformations. J Med Chem 59:592-608
Yang, Mingjun; Angles d'Ortoli, Thibault; Säwén, Elin et al. (2016) Delineating the conformational flexibility of trisaccharides from NMR spectroscopy experiments and computer simulations. Phys Chem Chem Phys 18:18776-94
Lemkul, Justin A; MacKerell Jr, Alexander D (2016) Balancing the Interactions of Mg(2+) in Aqueous Solution and with Nucleic Acid Moieties For a Polarizable Force Field Based on the Classical Drude Oscillator Model. J Phys Chem B 120:11436-11448
Khan, Hanif M; Grauffel, Cédric; Broer, Ria et al. (2016) Improving the Force Field Description of Tyrosine-Choline Cation-π Interactions: QM Investigation of Phenol-N(Me)4(+) Interactions. J Chem Theory Comput 12:5585-5595
Sarkar, Aurijit; Yu, Wenbo; Desai, Umesh R et al. (2016) Estimating glycosaminoglycan-protein interaction affinity: water dominates the specific antithrombin-heparin interaction. Glycobiology :
Soteras Gutiérrez, Ignacio; Lin, Fang-Yu; Vanommeslaeghe, Kenno et al. (2016) Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions. Bioorg Med Chem 24:4812-4825
Xu, You; MacKerell Jr, Alexander D; Nilsson, Lennart (2016) Structural effects of modified ribonucleotides and magnesium in transfer RNAs. Bioorg Med Chem 24:4826-4834

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