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Manganese metallosensor from mycobacterium tuberculosis – computational and experimental study

Manganese is an essential metal that is used in bacteria for basic cellular processes such as DNA replication and resistance to oxidative stress. On the other hand, manganese ions are toxic for the cell if present in high concentrations. Manganese homeostasis in bacteria Mycobacterium tuberculosis is regulated by MntR transcription factor. Bacteria M. tuberculosis is an intracellular pathogen that can cause tuberculosis. Since cellular mechanisms through which manganese homeostasis is regulated are different between bacteria and eukaryotes, M. tuberculosis MntR presents potential target for the development of novel antibiotics. Therefore, computational and experimental study that would enable understanding of M. tuberculosis MntR molecular mechanism could be valuable as fundamental scientific research, but might also have potential application in design of novel antibiotics. The first step in such study is a computational investigation of different forms of MntR transcription factor. Starting from available crystal structures [1], systems with and without manganese ions (Mn2+) present in the binding sites were prepared for molecular dynamics (MD) simulations. Since hydrogen bond networks in the protein structure might have an important role in allosteric response to the Mn2+ binding, different programs for adding polar hydrogen atoms were applied and different systems were subjected to the MD simulations. Differences in structural and dynamical properties of the MntR protein in such systems regarding the presence of Mn2+ ions were identified. Results of simulations indicated smaller fragments of complicated allosteric mechanism that is initiated by Mn2+ ions binding and will be experimentally validated. In experimental validation, NMR spectroscopy presents indispensable and highly valuable method since it allows validation of dynamical properties of the protein in various forms in solution.

Molecular dynamics simulations, manganese metallosensor, Mycobacterium tuberculosis

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