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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070855-12
Application #
9379467
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Lyster, Peter
Project Start
2005-09-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2019-11-30
Support Year
12
Fiscal Year
2018
Total Cost
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

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