Amyloid-β (Aβ) peptides aggregate spontaneously into various aggregating species comprising oligomers, protofibrils, and mature fibrils in Alzheimer's disease (AD). Disrupting β-sheet rich neurotoxic smaller soluble Aβ₄₂ oligomers formed at early stages is considered a potent strategy to interfere with AD pathology. Previous experiments have demonstrated the inhibition of the early stages of Aβ aggregation by baicalein; however, the molecular mechanism behind inhibition remains largely unknown. Thus, in this work, molecular dynamics (MD) simulations have been employed to illuminate the molecular mechanism of baicalein-induced destabilization of preformed Aβ₄₂ protofibrils. Baicalein binds to chain A of the Aβ₄₂ protofibril through hydrogen bonds, π–π interactions, and hydrophobic contacts with the central hydrophobic core (CHC) residues of the Aβ₄₂ protofibril. The binding of baicalein to the CHC region of the Aβ₄₂ protofibril resulted in the elongation of the kink angle and disruption of K28–A42 salt bridges, which resulted in the distortion of the protofibril structure. Importantly, the β-sheet content was notably reduced in Aβ₄₂ protofibrils upon incorporation of baicalein with a concomitant increase in the coil content, which is consistent with ThT fluorescence and AFM images depicting disaggregation of pre-existing Aβ₄₂ fibrils on the incorporation of baicalein. Remarkably, the interchain binding affinity in Aβ₄₂ protofibrils was notably reduced in the presence of baicalein leading to distortion in the overall structure, which agrees with the structural stability analyses and conformational snapshots. This work sheds light on the molecular mechanism of baicalein in disrupting the Aβ₄₂ protofibril structure, which will be beneficial to the design of therapeutic candidates against disrupting β-sheet rich neurotoxic Aβ₄₂ oligomers in AD.

中文翻译：

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使用计算机模拟深入了解黄芩素诱导的 LS 形 Aβ42 原纤维不稳定


在阿尔茨海默病 (AD) 中，β 淀粉样蛋白 (Aβ) 肽会自发聚集成各种聚集物质，包括寡聚体、原纤维和成熟原纤维。破坏早期形成的富含β-折叠的神经毒性较小的可溶性Aβ ₄₂ 寡聚体被认为是干扰AD病理的有效策略。之前的实验已经证明黄芩素可以抑制Aβ早期聚集；然而，抑制背后的分子机制仍然很大程度上未知。因此，在这项工作中，分子动力学（MD）模拟被用来阐明黄芩素诱导预先形成的Aβ ₄₂ 原纤维不稳定的分子机制。黄芩素通过氢键、π-π相互作用以及与 Aβ ₄₂ 原纤维中央疏水核心 (CHC) 残基的疏水接触与 Aβ ₄₂ 原纤维的 A 链结合。黄芩素与Aβ ₄₂ 原纤维CHC区域的结合导致扭结角伸长和K28-A42盐桥破坏，从而导致原纤维结构扭曲。重要的是，掺入黄芩素后，Aβ ₄₂ 原纤维中的 β-折叠含量显着降低，同时卷曲含量增加，这与描绘预先存在的 Aβ ₄₂ 原纤维的链间结合亲和力显着降低，导致整体结构扭曲，这与结构稳定性分析和构象快照一致。 这项工作揭示了黄芩素破坏 Aβ ₄₂ 原纤维结构的分子机制，这将有利于设计针对破坏富含 β-sheet 的神经毒性 Aβ ₄₂ 寡聚物的候选治疗药物在广告中。