記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/acs.langmuir.3c02459

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

<jats:p>Phosphatidylinositol (PI) lipids play a crucial role as a vital lipid component in cell membrane domain formation, contributing to cell signaling. In this study, we investigate the impact of PI lipids on the conformational dynamics of tubulin-associated unit (tau) fibrils through multiscale modelling. While prior experimental work by the Lecomte group has demonstrated the influence of PI lipids on the morphology and secondary structure of tau fragments, a detailed molecular understanding of the binding mechanism between tau and PI-incorporated lipids remains absent. Our molecular dynamics (MD) simulations reveal the intricate molecular mechanisms governing tau binding to PI-incorporated bilayers. Specifically, we conduct MD simulations on lipid patches containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (PC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (PG), enabling us to explore conformational changes in the R3--R4 section of tau fibrils. Control simulations are conducted on pure lipid patches without tau fibrils, as well as on tau fibrils within bulk water. Our findings demonstrate that PI-incorporated lipids exhibit a stronger affinity for binding to tau fibrils compared to pure PC/PG lipids. All-atom simulations highlight the potential docking sites for PI headgroups at positively charged residues (Lysine, Arginine) on the tau surface. Moreover, the aggregation of PI lipids facilitates tau binding to the membrane. These results not only enhance our comprehension of the disruption of PI-incorporated bilayers, but also shed light on the stability of the tau over the PI containing bilayers.</jats:p>

DOI： 10.1101/2023.09.20.558589

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

DOI： 10.1016/j.jmgm.2022.108398

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

Tau proteins are recently gaining a lot of interest due to their active role in causing a range of tauopathies. Molecular mechanisms underlying the tau interaction with the neuronal membrane are hitherto unknown and difficult to characterize using experimental methods. Using the cryo-EM structure of the tau-fibrils we have used atomistic molecular dynamics simulation to model the tau fibril and neuronal membrane interaction using explicit solvation. The dynamics and structural characteristics of the tau fibril with the neuronal membrane are compared to the tau fibril in the aqueous phase to corroborate the effect of the neuronal membrane in the tau structure. Tau fibrils have been modelled using CHARMM-36m force field and the six component neuronal membrane composition is taken from the earlier simulation results. The timescale conceivable in our molecular dynamics simulations is of the order of microseconds which captures the onset of the interaction of the tau fibrils with the neuronal membrane. This interaction is found to impact the tau pathogenesis that finally causes neuronal toxicity. Our study initiates the understanding of tau conformational ensemble in the presence of neuronal membrane and sheds the light on the significant tau-membrane interactions.

DOI： 10.1016/j.bpc.2023.107024

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

DOI： 10.1101/2022.02.16.480652

DOI： 10.1002/prot.26401

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