Computational modelling of the phosphorylation mechanism ATP and glucose

Walsh, Andrew (2018) Computational modelling of the phosphorylation mechanism ATP and glucose. Masters thesis, Memorial University of Newfoundland.

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Abstract

Microbes have found ways to render certain drugs ineffective and hence are no longer susceptible to them. Continued misuse of a wide variety of drugs has given rise to organisms being able to resist them, which has led to multidrug resistance. One way to solve the issue of multidrug resistance is by looking at the mechanism of phosphorylation using adenosine triphosphate (ATP) the phosphate donor. If the phosphorylation of antibiotics can be prevented from occurring, then they would retain their antibacterial activity and thus help solve the issue of drug modification by bacteria. The two-step mechanism for the phosphorylation of glucose using ATP, in which ATP is dephosphorylated in the first step and glucose is phosphorylated in the second step, is investigated using Hartree-Fock (HF) and B3LYP calculations with the 6-31G(d) and 6-31+G(d) basis sets. Glucose is chosen for study since it is a simple model for kanamycin. The ability of each conformer of ATP to donate a phosphate group is also discussed. The phosphorylation of both the alpha and beta anomers of glucose as well as the ᴅ and ʟ enantiomers of glucose is also discussed. It was determined that, while the chairPT isomer of ⁴⁻ is lower in energy than the chair isomer of ATP⁴⁻, the ΔUᵣₓn, ΔHᵣₓn and ΔGᵣₓn values are less negative for the phosphorylation of the chair isomer of ATP⁴⁻. The ΔUᵣₓn, ΔHᵣₓn and ΔGᵣₓn values are least positive for the phosphorylation of deprotonated β-ʟ-glucose without water while they are least positive for the phosphorylation of deprotonated α-ʟ-glucose upon inclusion of water molecules.

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