Computational prediction of factors affecting the stability of tau fibrils
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| Year of publication | 2024 |
| Type | Conference abstract |
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| Description | 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 ß-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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