| Description |
The hallmark of neurodegenerative diseases is the abnormal accumulation of tau protein, transforming it from a soluble state into insoluble aggregates with unique structures depending on the disease [1]. Understanding the exact molecular mechanisms behind this aggregation and how post-translational modifications influence it still remains a significant challenge for experimental research. To address this, we employ computational approaches, specifically utilizing three variations of molecular dynamics simulations [2, 3], to thoroughly investigate the fibrillization process of paired helical filaments observed in Alzheimer's disease [4] and chronic traumatic encephalopathy type II [5]. Our results demonstrate that tau aggregation into these paired helical filaments predominantly occurs at one end of the fibril, with considerable energetic differences for dissociation from the two ends. Furthermore, phosphorylation (pSer324/pSer324 and pSer356) decreased the free energy minimum of the fibril, showing cooperation of these phosphorylations in the fibril stabilization. While histidine 329 protonation also contributes to fibril stabilization in both diseases, the impact of histidine 374 protonation differs between the two conditions. 1. Lövestam, S., Li, D., Wagstaff, J. L., Kotecha, A., Kimanius, D., McLaughlin, S. H., Murzin, A. G., Freund, S. M. V., Goedert, M., & Scheres, S. H. (2024). Disease-specific tau filaments assemble via polymorphic intermediates. Nature, 625(7993), 119-125. 2. Leonard, C., Phillips, C., & McCarty, J. (2021). Insight into seeded tau fibril growth from Molecular Dynamics simulation of the Alzheimer’s disease protofibril core. Frontiers in molecular biosciences, 8, 624302. 3. Liu, H., Liu, X., Zhou, S., An, X., Liu, H., & Yao, X. (2019). 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), 1854-1865. 4. Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H. J., Crowther, R. A., Ghetti, B., Goedert, M., & Scheres, S. H. W. (2017). Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature, 547(7662), 185-190. 5. Falcon, B., Zivanov, J., Zhang, W., Murzin, A. G., Garringer, H. J., Vidal, R., Crowther, R. A., Newell, K. L., Ghetti, B., Goedert, M., & Scheres, S. H. (2019). Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature, 568(7752), 420-423
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