Informace o publikaci
QM/MM Reaction Simulations of Alpha-(1,3)-fucosyltransferase of Helicobacter pylori
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| Rok publikování | 2024 |
| Druh | Konferenční abstrakty |
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| Popis | Helicobacter pylori is a severe human pathogen associated with many gastrointestinal disorders, such as chronic gastric inflammation, ulcers, and cancer. Due to the rise of antibiotic resistance, its treatment has become increasingly more challenging, accelerating the search for novel antibacterial agents. In this study, we focus on H. pylori alpha-(1,3)-fucosyltransferase FutA, an essential enzyme in the biosynthesis of Lewis antigens, which camouflages the bacteria from the host's immune system. Thus, FutA represents an attractive pharmacological target for developing novel transition state inhibitors. The exact reaction mechanism of FutA is currently unknown. The X-ray crystal structure of FutA has been solved with the donor substrate only. Moreover, the active site is wide open, suggesting a large conformational change must occur upon the acceptor binding. Employing molecular modelling, we have found several closed enzyme conformations containing both the donor and acceptor ligands in an orientation suitable for the reaction. We started with AlphaFold2 to obtain a suitable model for docking simulations. Using simulated annealing with carefully designed distance restraints for docking, we positioned both substrates in their respective binding sites. Next, we simulated a large conformational change upon the binding of the substrates, confirming the hypothesis that the enzyme must undergo a significant conformational change before the reaction occurs. Here, we will report the results of QM/MM simulations employing steered molecular dynamics (SMD) for the free energy calculations. These simulations aim to validate the suitability of our pre-reaction complexes for the reaction simulations. We investigated the effects of the QM region size, the impact of chosen collective variables, and the level of QM theory on calculated reaction profiles. |
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