Carbohydrates are the most abundant biopolymers on earth. Their biological functions include fuels, energy storage, metabolic intermediates, structural roles and, importantly, molecular recognition, including roles in vaccines, cell-cell recognition and the pathogenic activity of bacterial toxins. Accordingly, detailed knowledge of carbohydrate structure-function relationships would allow for better understanding of a variety of biological phenomena. To explore these structure-function relationships theoretical approaches offer great potential. The proposed study will enhance both our understanding of the structural properties of carbohydrates as well as the utility of theoretical methods in studying carbohydrates, especially those involved in molecular recognition. These goals will be achieved by first investigating the gauche and anomeric effects, known to be important for the conformational properties of mono- and disaccharides, via quantum mechanical (QM) calculations. Information from the QM calculations will lay the groundwork for the development of an empirical force field for carbohydrates that is compatible with the CHARMM force fields for proteins, lipids and nucleic acids, thereby allowing for computational studies of carbohydrates in heterogeneous systems including glycoproteins and glycolipids. The optimized force field parameters will be validated via molecular dynamics (MD) simulation studies of biologically interesting carbohydrate-containing systems for which experimental data are available. Upon completion of the proposed study a better understanding of the structural properties of carbohydrates, ranging for monosaccharides, polysaccharides and carbohydrates in heterogeneous systems, including vaccines and bacterial toxins, will be obtained. In addition, a new empirical force field for carbohydrates will be made available to the scientific community. The availability of a carbohydrate force field that is compatible with available force fields for proteins, lipids and nucleic acids will greatly enhance the applicability of computational approaches to these biologically essential molecules, facilitating the rational design of therapeutic agents, vaccines and counterterrorism agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070855-04
Application #
7485650
Study Section
Special Emphasis Panel (ZRG1-BCMB-Q (02))
Program Officer
Wehrle, Janna P
Project Start
2005-09-01
Project End
2010-06-30
Budget Start
2008-09-01
Budget End
2010-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$238,989
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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
Lemkul, Justin A; MacKerell Jr, Alexander D (2018) Polarizable force field for RNA based on the classical drude oscillator. J Comput Chem 39:2624-2646
Huang, Jing; Lemkul, Justin A; Eastman, Peter K et al. (2018) Molecular dynamics simulations using the drude polarizable force field on GPUs with OpenMM: Implementation, validation, and benchmarks. J Comput Chem 39:1682-1689
Aytenfisu, Asaminew H; Yang, Mingjun; MacKerell Jr, Alexander D (2018) CHARMM Drude Polarizable Force Field for Glycosidic Linkages Involving Pyranoses and Furanoses. J Chem Theory Comput 14:3132-3143
Aleksandrov, Alexey; Lin, Fang-Yu; Roux, BenoƮt et al. (2018) Combining the polarizable Drude force field with a continuum electrostatic Poisson-Boltzmann implicit solvation model. J Comput Chem 39:1707-1719
Khan, Hanif Muhammad; MacKerell, Alexander D; Reuter, Nathalie (2018) Cation-? interactions between methylated ammonium groups and tryptophan in the CHARMM36 additive force field. J Chem Theory Comput :
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
Re, Suyong; Watabe, Shigehisa; Nishima, Wataru et al. (2018) Characterization of Conformational Ensembles of Protonated N-glycans in the Gas-Phase. Sci Rep 8:1644
Lin, Fang-Yu; Lopes, Pedro E M; Harder, Edward et al. (2018) Polarizable Force Field for Molecular Ions Based on the Classical Drude Oscillator. J Chem Inf Model 58:993-1004

Showing the most recent 10 out of 92 publications