DataSheet1_Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study.doc

Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the β-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered β-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.

微管相关蛋白tau的异常聚集与tauopathies（如阿尔茨海默病和慢性创伤性脑病）密切相关。tau蛋白的六肽275VQIINK280（PHF6*）作为tau蛋白的纤维原核核心基序，已被证实其在tau蛋白聚集过程中扮演着至关重要的角色。累积的实验证据表明，PHF6*中的单个赖氨酸残基K280的乙酰化是形成病理性的tau蛋白淀粉样沉积的关键事件。然而，K280乙酰化如何影响tau蛋白在原子层面的聚集的潜在机制尚不清楚。在本研究中，我们通过复制交换分子动力学模拟来探究K280乙酰化对PHF6*聚集的影响。我们的模拟结果显示，K280的乙酰化不仅增强了PHF6*肽的自组装能力，还增加了PHF6*的β-折叠结构倾向。K280的乙酰化增强了PHF6*肽之间的分子间相互作用，导致PHF6*聚集体中有序β-折叠富集构象的增加以及结构多样性的降低。残基对接触频率分析显示，K280的乙酰化增加了PHF6*肽中疏水化学基团之间的相互作用，从而促进了PHF6*的聚集。本研究对乙酰化对PHF6*聚集的影响提供了机制上的见解，有助于深入理解乙酰化与tau蛋白在分子层面的聚集之间的关联。