PhD study/position: Structural and thermodynamic properties of protein fibrils relevant in neurodegeneration. Free energy calculations.

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

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

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

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)

The CEITEC PhD School is based on the so-called "Principles for Innovative Doctoral Training" issued by the European Union to standardise the quality of European doctoral studies. These principles include excellent science, an attractive institutional environment, opportunities for interdisciplinary research, collaboration with industry and potential employers, gaining international experience and contacts, and developing transferable skills and soft skills.

Requirements on candidates

• preferable candidate’s background in biophysics, computational chemistry, or physical chemistry