Computational prediction of factors affecting the stability of tau fibrils

IĽKOVIČOVÁ, Lucia a Jozef HRITZ. Computational prediction of factors affecting the stability of tau fibrils. In XXIII. meeting of biochemists and molecular biologists. 2024.

Základní údaje

Originální název

Computational prediction of factors affecting the stability of tau fibrils

Autoři

IĽKOVIČOVÁ, Lucia ORCID a Jozef HRITZ

Vydání

XXIII. meeting of biochemists and molecular biologists, 2024

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Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Stát vydavatele

Česká republika

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Označené pro přenos do RIV

Ne

Organizační jednotka

Středoevropský technologický institut

Klíčová slova česky

tau protein, párové helikální filamenty, fosforylace, molekulová dynamika, volné energie

Klíčová slova anglicky

tau protein, paired helical filaments, phosphorylation, molecular dynamics, free energies

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Anotace

V originále

Alzheimer’s disease, chronic traumatic encephalopathy and others belong to the group of neurodegenerative diseases called tauopathies. Each of them is characterized by a specific type of tau protein fibrils composed of β-sheets arranged in a defined fold [1]. Tau protein is an intrinsically disordered microtubule-associated protein whose primary function is the stabilization and regulation of the microtubules. Upon phosphorylation, the tau protein detaches from the microtubules and depending on the phosphorylation patterns and other conditions, it may aggregate into the fibrils. The study of the tau aggregation mechanism experimentally is still a challenging task. Molecular dynamics (MD) simulations provide us with a helpful insight into the dynamics of the fibrils [2,3]. Intrinsically disordered proteins (IDPs) usually require special parametrization of the force field for the MD [3]. However, little is known about the proper simulation parameters for fibrils composed of IDPs in MD. In this study, we explore the effect of protonation on histidine, selection of water model and other properties of the simulation system on the paired helical filaments from Alzheimer’s disease [4] and chronic traumatic encephalopathy type II fibrils [5]. We believe that properly validated computational simulations of the tau fibrilization can provide important mechanistic insights in the process of pathological changes and inspire the design of future experiments in this area. [1] Lövestam, Sofia, et al. "Disease-specific tau filaments assemble via polymorphic intermediates." Nature 625.7993 (2024): 119-125. [2] Liu, Hongli, et al. "Disclosing the template-induced misfolding mechanism of tau protein by studying the dissociation of the boundary chain from the formed tau fibril based on a steered molecular dynamics simulation." ACS Chemical Neuroscience 10.3 (2019): 1854-1865. [3] Zapletal, Vojtěch, et al. "Choice of force field for proteins containing structured and intrinsically disordered regions." Biophysical journal 118.7 (2020): 1621-1633. [4] Fitzpatrick, Anthony WP, et al. "Cryo-EM structures of tau filaments from Alzheimer’s disease." Nature 547.7662 (2017): 185-190. [5] Falcon, Benjamin, et al. "Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules." Nature 568.7752 (2019): 420-423.

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Návaznosti

MUNI/C/0059/2024, interní kód MU	Název: Vypočetní simulace agreagace tau proteinu Investor: Masarykova univerzita, Vypočetní simulace agreagace tau proteinu, Podpora vynikajících diplomových prací
101087124, interní kód MU	Název: Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe Investor: Evropská unie, Alzheimer's Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe, Rozšiřování účasti a posílení ERA
90254, velká výzkumná infrastruktura	Název: e-INFRA CZ II