Date of Award


Publication Type

Doctoral Thesis

Degree Name



Chemistry and Biochemistry

First Advisor

James W. Gauld


Pure sciences, Carbohydrates, Computational chemistry, Enzymology, Theoretical



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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.


As the most abundant class of biological molecules, carbohydrates are essential to all living organisms. Their derivatives play a variety of important roles in biological systems. In this thesis, carbohydrate-related biochemistry is investigated using various computational methods.

Chapter 1 presents an overview of the problems addressed in this thesis, and Chapter 2 discusses various theoretical methods.

Chapter 3 is an investigation on the NAD+ -dependent oxidation mechanism of UDP-glucose dehydrogenase (UDPGlcDH), a target for the development of new antibacterial drugs. A large enzyme active-site modelling approach was used in the investigation of the mechanism.

Chapter 4 is a DFT investigation on how 6-Phospho-α-glucosidase (GlvA) exploits the inherent properties of modified sugar-rings that dramatically enhance the rate of glycosidic bond cleavage process. The driving-force of the mechanism and enzyme regioselectivity were explained using natural bond orbital theory (NBO) and second-order perturbation analyses.

Chapter 5 is a computational investigation, involving Docking and MD methods, to elucidate substrate binding within the active site of LuxS. In particular, we aim to determine the substrate binding conformations in the enzyme active site and the first stage of the enzyme mechanism.

Chapter 6 is a quantum mechanics/molecular mechanics (QM/MM) and DFT investigation on the catalytic mechanism of the flavoenzyme UDP-Galactopyranose Mutase (UGM). A complete understanding of its mechanism can potentially enable the development of new TB therapeutic drugs. We studied two enzyme active-site models with a protonated or neutral Histidine residue using DFT cluster approach. Then, a QM/MM-based approach was used to include the steric and non-homogeneous polar environment of the enzyme's active site.

Chapter 7 presents a new type of substrate assisted-mechanism that was proposed for aminoacyl tRNA synthetase, an essential step in protein synthesis. Our DFT calculation results indicated that the neutral amine group on the substrate could act as the required general base in the mechanism. This is the first time that such a substrate assisted catalytic mechanism has been proposed for this presumably ancient class of enzymes.

Finally, Chapter 8 summarizes the main conclusions and possible extensions of the current work.

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