HomePh.D. Study at IOCBTopics 2019Physical and Computational Chemistry

Physical and Computational Chemistry

Tutor Dr. Vladimír Sychrovský

Petr Bouř

Topic Theoretical Modeling of Catalytic Mechanism of the DNA Repair Enzymes
Faculty MFF UK

Serious sequel to organism may occur due to the corrupted function of nucleic acids upon their damage. The repair of damaged DNA operated by the base-excision repair enzymes (BER enzymes) is closely related to autonomous therapeutic pathways that ensure basal chemical processes in cell. The discovery of BER was recently awarded by the Nobel price. Although several BER enzymes targeting particular damages of DNA were described up to date, their catalytic mechanisms remained largely unknown. Our recent study on the function of the human 8-oxoguanine DNA glycosylase 1 (hOGG1) BER enzyme highlighted new facts concerning the catalytic excision of 8-oxo-2′-deoxyguanosine (8-oxo-G) that arises due to damage of normal guanosine. 8-oxo-G is one of the most frequently occurring and dangerous lesions due to the oxidative damage to DNA that can occur normally within respiratory pathways in cell and upon unwanted chemicals. The PhD project will be focused on theoretical research of hOGG1 and other BER enzymes by employing the methods of theoretical chemistry such as QM, QM/MM and MD for calculations of physicochemical properties of DNA-BER enzyme complex including NMR spectroscopic parameters. The theoretical calculations will be used for interpretation of experiments conducted in Czech and Japanese laboratories.

Leading references
1. Šebera, J., et al. Pyramidalization of the Glycosidic Nitrogen Provides the Way for Efficient Cleavage of the N-Glycosidic Bond of 8-OxoG with the hOGG1 DNA Repair Protein, Journal of Physical Chemistry B, 116, (2012), pp 12535-12544.
2. Šebera, J., et al. The mechanism of the glycosylase reaction with hOGG1 base-excision repair enzyme: concerted effect of Lys249 and Asp268 during excision of 8-oxoguanine”, Nucleic Acids Res., 45, (2017), pp 5231-5242.