Přehled

Doctoral study program
Life Sciences (Faculty of Science, Masaryk University)

Research area
structural biology, computational simulations, conformations of proteins, protein aggregation, brain disorders

Supervisor
doc. RNDr. Mgr. Jozef Hritz, Ph.D.

Annotation
The main neuropathological signs of Alzheimer’s disease are associated with the fibrillization of tau protein into neurofibrillary tangles. The growing number of Tau fibrils allow the structural and stability elucidations Studying how different factors influence the formation of protein fibrils is the key to understanding these neurodegenerative processes. The main aim of this PhD project will be computational simulations of structural changes leading to the fibril form of selected proteins (Tau, a-Syn, Abeta) and the corresponding free energy profiles along such pathways. The impact of phosphorylation, buffer conditions, truncation, or the interaction with the client proteins like 14-3-3s will be addressed. The obtained computational data will be validated by biophysical experimental techniques.

Recommended literature
Kitoka K, Lends A, Kučinskas G, Bula AL, Krasauskas L, Smirnovas V, Zilkova M; Kovacech B, Skrabana R, Hritz J, Jaudzems K*: dGAE(297-391) tau fragment promotes formation of CTE-like full-length tau filaments, Angew. Chem. Int. Ed. 2024, e202407821
Crha R., Kozeleková A., Hofrová A., Iľkovičová L., Gašparik N., Kadeřávek P., Hritz J.*: Hiding in plain sight: Complex interaction patterns between Tau and 14-3-3ζ protein variants. . Int. J. Biol. Macromol. 2024, 266, 130802
Lasorsa A., Bera K., Malki I., Dupré E., Cantrelle F., Merzougui H., Sinnaeve D., Hanoulle X., Hritz J.*, Landrieu I.*: Conformational impact of multiple phosphorylations within BIN1 SH3 domain binding site in the proline rich region of Tau protein. Biochemistry 2023, 62, 1631–1642
Trosanova Z., Lousa P., Kozelekova A., Brom T., Gasparik N., Tungli J., Weisova V., Zupa E., Zoldak G., Hritz J.*: Quantitation of human 14-3-3ζ dimerization and the effect of phosphorylation on dimer-monomer ekvilibria. J. Mol. Biol. 2022, 434, 167479
Zapletal, V.; Mládek, A.; Melková, K.; Louša, P.; Nomilner, E.; Jaseňáková, Z.; Kubáň, V.; Makovická, M.; Laníková, A.; Žídek L.; Hritz, J.* Choice of force field for proteins containing structured and intrinsically disordered regions. Biophys. J. 2020, 118, 1621 – 1633
Jandova Z; Trosanova Z.; Weisova V.; Oostenbrink C., Hritz J.*: Free energy calculations on the stability of the 14-3-3z protein. BBA – Proteins and Proteomics, 2018, 1866, 442-450
Nagy G., Oostenbrink C., Hritz J.*: Exploring the Binding Pathways of the 14-3-3z Protein: Structural and Free-Energy Profiles Revealed by Hamiltonian Replica Exchange Molecular Dynamics with Distance Field Distance Restraints. PLoS ONE 2017,12(7), e0180633
Funding
2023 – 2026: Horizont Evropa: HORIZON-WIDERA-2022-ACCESS-04 (ID: 68358): Alzheimer’s Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe (ADDIT-CE)

2024-2027: MŠMT JPND (ID:9F24003): Spatiotemporal transcriptome and proteome analysis of Synuclein pathology in Parkinson’s disease: Identification of cell type-specific vulnerability and tolerance mechanisms (4DPD-Omics)

2020 – 2025: mobility grant H2020-MSCA-RISE-2019 InterTau (ID: 873127): Integrative structural biology of pathological tau protein, an appealing therapeutic target for Alzheimer´s disease (InterTau)

Requirements on candidates
preferable candidate’s background in biophysics, computational chemistry, or physical chemistry

Keywords
computational simulations, free energy calculations, thermodynamics, Tau protein, a-Syn, neurodegenerative diseases

Information about the application process
https://www.ceitec.eu/ls-mm-phd/

Application webpage
https://www.ceitec.eu/structural-and-thermodynamic-properties-of-protein-fibrils-relevant-in-neurodegeneration-free-energy-calculations/t11437