School of Chemical Sciences, National Institute of Science Education & Research-Bhubaneswar, An OCC of Homi Bhabha National Institute, P.O. Jatni, Khurda, Odisha 752050, India.
School of Chemical Sciences, National Institute of Science Education & Research-Bhubaneswar, An OCC of Homi Bhabha National Institute, P.O. Jatni, Khurda, Odisha 752050, India.
Biophys Chem. 2023 Jul;298:107024. doi: 10.1016/j.bpc.2023.107024. Epub 2023 Apr 21.
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.
由于在引起一系列tau 病中的积极作用，tau 蛋白近来受到了广泛关注。tau 与神经元膜相互作用的分子机制目前尚不清楚，并且使用实验方法难以进行表征。我们使用 tau 原纤维的冷冻电镜结构，通过使用显式溶剂化的原子分子动力学模拟，来模拟 tau 原纤维与神经元膜的相互作用。将与神经元膜相互作用的 tau 原纤维的动力学和结构特征与水相中的 tau 原纤维进行比较，以证实神经元膜对 tau 结构的影响。tau 原纤维使用 CHARMM-36m 力场进行建模，六组分神经元膜组成取自早期的模拟结果。在我们的分子动力学模拟中，可以想象的时间尺度约为微秒，这可以捕捉到 tau 原纤维与神经元膜相互作用的开始。这种相互作用被发现会影响导致神经元毒性的 tau 发病机制。我们的研究开始了解神经元膜存在下 tau 的构象集合，并阐明 tau 与膜的重要相互作用。
