Department of Chemistry, Faculty of Basic and Applied Sciences, Sri Guru Granth Sahib World University, Fatehgarh Sahib-140406, Punjab, India.
Department of Chemistry, DAV College, Sector 10, Chandigarh-160011, India.
Phys Chem Chem Phys. 2024 Jun 12;26(23):16674-16686. doi: 10.1039/d3cp06006c.
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 Aβ 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 Aβ protofibrils. Baicalein binds to chain A of the Aβ protofibril through hydrogen bonds, π-π interactions, and hydrophobic contacts with the central hydrophobic core (CHC) residues of the Aβ protofibril. The binding of baicalein to the CHC region of the Aβ 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 Aβ 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 Aβ fibrils on the incorporation of baicalein. Remarkably, the interchain binding affinity in Aβ 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 Aβ protofibril structure, which will be beneficial to the design of therapeutic candidates against disrupting β-sheet rich neurotoxic Aβ oligomers in AD.
淀粉样蛋白-β（Aβ）肽在阿尔茨海默病（AD）中自发聚集形成各种聚集物，包括低聚物、原纤维和成熟纤维。干扰早期形成的富含β-折叠的神经毒性较小可溶性 Aβ低聚物被认为是干扰 AD 病理学的有效策略。先前的实验已经证明了白杨素抑制 Aβ 聚集的早期阶段；然而，抑制背后的分子机制在很大程度上仍然未知。因此，在这项工作中，采用分子动力学（MD）模拟来阐明白杨素诱导的 Aβ原纤维不稳定的分子机制。白杨素通过氢键、π-π相互作用和与 Aβ原纤维中心疏水区（CHC）残基的疏水接触与 Aβ原纤维的链 A 结合。白杨素与 Aβ原纤维的 CHC 区域结合导致扭角伸长和 K28-A42 盐桥的破坏，从而导致原纤维结构的变形。重要的是，在 Aβ原纤维中加入白杨素后，β-折叠含量明显降低，同时螺旋含量增加，这与 ThT 荧光和 AFM 图像一致，这些图像显示在加入白杨素后，预先存在的 Aβ纤维的解聚。值得注意的是，在存在白杨素的情况下，Aβ原纤维中的链间结合亲和力显著降低，导致整体结构变形，这与结构稳定性分析和构象快照一致。这项工作阐明了白杨素破坏 Aβ原纤维结构的分子机制，这将有助于设计针对破坏富含β-折叠的神经毒性 Aβ低聚物的治疗候选物。
