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Conformational analysis of galactofuranosides using NMR spectroscopy and computational chemistry Open Access


Other title
Carbohydrate NMR
Molecular modeling
Conformational Analysis
Type of item
Degree grantor
University of Alberta
Author or creator
Richards, Michele R.
Supervisor and department
Lowary, Todd L. (Chemistry, UofA)
Examining committee member and department
Brown, Alex (Chemistry, UofA)
Gibbs-Davis, Julianne M. (Chemistry, UofA)
Moitessier, Nicolas (Chemistry, McGill)
Choi, Phillip Y. K. (Chemical and Materials Engineering, UofA)
Department of Chemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
The five-membered ring, or furanose, form of galactose is not found in mammalian systems. However, it is commonly found in pathogenic organisms, including Aspergillus fumigatus, Campylobacter jejuni, and Mycobacterium tuberculosis. In many of these organisms, galactofuranose (Galf) is essential for virulence or viability. For example, a major component of the mycobacterial cell-wall is the mycolyl-arabinogalactan (mAG) complex, which contains 30–35 alternating β-(1-5)- and β-(1-6)-linked Galf moieties. The enzyme that synthesizes most of the galactan portion of mAG, GlfT2, is bifunctional, forming both β-(1-5)- and β-(1-6)-bonds in a single active site. The exact mechanism of the regiochemistry of bond formation catalyzed by GlfT2 has not been established, but accurate predictions of the conformation of short galactan oligomers would allow us to determine key carbohydrate-protein interactions with these furanose sugars. The inherent flexibility of the furanose ring makes it difficult to model with current methods. This thesis presents improved tools for determining the conformation of the monosaccharides, methyl α- and β-D-Galf, as well as Galf-containing trisaccharides, which are model systems for the mycobacterial mAG complex. Specifically, we have evaluated the gas-phase the potential energy surfaces (PES) for both monosaccharides. We then compared the low energy conformations from the PES to the solution-state conformation determined from nuclear magnetic resonance (NMR) spectra and the program PSEUROT. For the α-anomer, there was good agreement between the gas-phase conformation and the PSEUROT results; however, the PSEUROT approach failed for the β-anomer. To overcome the limitations in PSEUROT, we turned to molecular dynamics (MD) simulations of the monosaccharides. Average vicinal proton–proton coupling constants were determined from the MD simulations, via newly developed Galf-specific Karplus relationships. Most of the calculated vicinal coupling constants agreed well with the corresponding experimental values, except those for the C4–C5 bond. Therefore, we adjusted the force field terms associated with this bond, and the new parameters improved the agreement between experiment and simulation for C4–C5 bond in the monosaccharides. However, the new terms did not affect the C4–C5 bond for β-(1-5)-linked residues in the Galf-containing trisaccharides.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Richards, M. R.; Lowary, T. L. ChemBioChem 2009, 10, 1920–1938.

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