Recent studies in Alzheimer's disease (AD) investigated the precise mechanisms responsible for neurofibrillary tangles (NFT) and senile plaques formation. NFTs, the aggregated Tau protein isoforms, are one of the primary factors behind AD. The corresponding smallest variant Tau43, as paired helical filaments (PHFs), self-assemble into pathological diseased aggregates. However, the molecular details in rationalizing the aggregation propensity of Tau43 remain elusive. Herein, using molecular dynamics simulations on aqueous Tau43, we identify the molecular factors responsible for early behavior of Tau43 aggregation propensity in water. The variant is intrinsically unstructured yet compact in nature, in agreement with previous studies. The PHF6 (¹¹VQIVYK¹⁶) segment is relatively less fluctuating, yet most extended and hydrophobic, thereby shielded from aqueous environment by intermolecular polar interactions between terminal residues. We also compared structural propensities of Tau43 and oppositely charged Aβ42 peptide, providing a comparative understanding of early AD pathway, leading to corresponding drug designing avenues.

中文翻译：

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Tau43 在水中早期聚集的原子水平研究 I. 单体 Tau43 的构象倾向

最近对阿尔茨海默病 (AD) 的研究调查了导致神经原纤维缠结 (NFT) 和老年斑形成的精确机制。NFTs，聚合的 Tau 蛋白同种型，是 AD 背后的主要因素之一。相应的最小变体 Tau43，作为成对螺旋丝 (PHF)，自组装成病理性病变聚集体。然而，使 Tau43 的聚集倾向合理化的分子细节仍然难以捉摸。在此，我们使用 Tau43 水溶液的分子动力学模拟，确定了导致 Tau43 在水中聚集倾向早期行为的分子因素。与先前的研究一致，该变体本质上是非结构化的，但本质上是紧凑的。PHF6 ( ¹¹ VQIVYK ¹⁶) 段的波动相对较小，但大部分延伸和疏水，从而通过末端残基之间的分子间极性相互作用与水性环境隔离。我们还比较了 Tau43 和带相反电荷的 Aβ42 肽的结构倾向，提供了对早期 AD 通路的比较理解，导致相应的药物设计途径。