Amyloid β (Aβ) senile plaques and Tau neurofibrillary tangles (NFTs) are major hallmarks of Alzheimer's disease (AD). However, early stages of Tau aggregation are still limitedly recognized. Here, we present atomistic molecular dynamics simulations and thermodynamics characterizations of heterogeneous Tau43-Aβ42 and homogeneous Tau43-Tau43 dimerization processes. Two-stage approaching-accommodation mechanism after individual diffusive regime is observed. The approach step involves opposing forces driving two distant monomers to come closer to each other, which are the decrease in protein internal and water-induced energies, respectively. In the accommodation step, a decrease in protein internal energy is the main driving force for stable compact structure formation. While the charged residues differently initiate and stabilize the dimer structures, the hydrophobic residues (¹¹VQIVYK¹⁶ in Tau43 and ³⁹VVIA⁴² in Aβ42) facilitate the formation of compact dimers, in agreement with experiments. Our results of Tau43-Aβ42 and Tau43-Tau43 dimerization will illuminate early onset mechanisms of AD pathology and corresponding therapeutic initiatives.

中文翻译：

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Tau43 在水中早期聚集的原子水平研究 II。Tau43-Aβ42 与 Tau43-Tau43 二聚化

淀粉样蛋白 β (Aβ) 老年斑和 Tau 神经原纤维缠结 (NFT) 是阿尔茨海默病 (AD) 的主要标志。然而，对 Tau 聚集的早期阶段的认识仍然有限。在这里，我们展示了异质 Tau43-Aβ42 和均质 Tau43-Tau43 二聚化过程的原子分子动力学模拟和热力学表征。观察到个体扩散机制后的两阶段接近调节机制。接近步骤涉及相反的力，驱使两个遥远的单体彼此靠近，这分别是蛋白质内部能量和水诱导能量的减少。在调节步骤中，蛋白质内能的降低是形成稳定致密结构的主要驱动力。与实验一致，Tau43 中的¹¹ VQIVYK ¹⁶和Aβ42 中的³⁹ VVIA ⁴² ) 促进紧凑二聚体的形成。我们的 Tau43-Aβ42 和 Tau43-Tau43 二聚化结果将阐明 AD 病理学的早期发病机制和相应的治疗举措。