Helicobacter pylori is a severe human pathogen associated with several gastrointestinal disorders, including gastric inflammation, ulcers, and cancer. However, its primary treatment using antibiotics has become increasingly more challenging because of the emergence of antibiotic resistance. As a result, there is a growing need for novel antibacterial agents. In order to design such new compounds, it is necessary to thoroughly understand the fundamental biochemical processes that could serve as therapeutic targets. In this work, we will study the reaction mechanism of H. pylori glycosyltransferase FucT. FucT is an essential enzyme in the biosynthesis of type II blood group antigens that are thought to mask the bacteria from the host’s immune system. However, the experimental structure of the fully active complex is not known.
We will first characterise the enzyme structure, utilising the ab initio protein structure prediction program Alphafold2. In the next challenging part, we will prepare the enzyme-substrates complex in silico by positioning the substrates into their correct location in the active site. Finally, we will use state-of-the-art hybrid QM/MM simulations to characterise the reaction pathway, determine the reaction mechanism and identify the transition state. The reaction pathway and especially the transition state geometry could then become the starting point for the rational design of transition state mimetics that could become a part of new treatment options for H. pylori infections.

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