Biomedical Engineering Graduate Program , University of New Mexico , Albuquerque , New Mexico 87131 , United States.
Center for Biomedical Engineering , University of New Mexico , Albuquerque , New Mexico 87131 , United States.
J Phys Chem B. 2019 Jan 24;123(3):551-560. doi: 10.1021/acs.jpcb.8b09185. Epub 2019 Jan 9.
Oligomeric aggregates of the amyloid-β (Aβ) peptide are believed to be the primary toxic species that initiate events leading to neurodegeneration and cognitive decline in Alzheimer's disease (AD). Small molecules that interfere with Aβ aggregation and/or neurotoxicity are being investigated as potential therapeutics for AD, including naturally occurring polyphenols. We have recently shown that curcumin exerts a neuroprotective effect against Aβ40-induced toxicity on cultured neuronal cells through two possible concerted pathways, ameliorating Aβ oligomer-induced toxicity and inducing the formation of nontoxic Aβ oligomers, both of which involve curcumin binding to Aβ oligomers. To gain molecular-level insights into curcumin's interaction with Aβ oligomers, we use all-atom molecular dynamics (MD) simulations to study the dynamics and energetics of curcumin binding to an Aβ protofibril composed of 24 peptides. Our results show that curcumin binds to specific hydrophobic sites on the protofibril surface and that binding is generally associated with the concomitant complexation of curcumin into dimers, trimers, or tetramers. Curcumin also binds to the protofibril growth axis ends but without complexation. Analysis of the energetics of the binding process revealed that curcumin complexation contributes in an additive fashion to curcumin-Aβ protofibril interactions. Favorable curcumin-protofibril binding is driven by a combination of hydrophobic interactions between curcumin and protofibril, curcumin self-aggregation, and solvation effects. These interactions are likely critical in blocking Aβ oligomer toxicity and inducing the growth of the protofibrils into "off-pathway" wormlike fibrils observed experimentally.
寡聚体聚集的淀粉样蛋白-β（Aβ）肽被认为是主要的毒性物质，引发了导致阿尔茨海默病（AD）神经退行性变和认知能力下降的事件。干扰 Aβ聚集和/或神经毒性的小分子被作为 AD 的潜在治疗药物进行研究，包括天然存在的多酚。我们最近表明，姜黄素通过两种可能的协同途径对 Aβ40 诱导的培养神经元细胞毒性发挥神经保护作用，改善 Aβ寡聚物诱导的毒性并诱导形成无毒的 Aβ寡聚物，这两种途径都涉及姜黄素与 Aβ寡聚物的结合。为了深入了解姜黄素与 Aβ寡聚物的相互作用，我们使用全原子分子动力学（MD）模拟来研究姜黄素与由 24 个肽组成的 Aβ原纤维的动力学和能量学。我们的结果表明，姜黄素结合到原纤维表面的特定疏水区，并且结合通常与姜黄素同时复合成二聚体、三聚体或四聚体相关。姜黄素也结合到原纤维生长轴的末端，但没有复合。对结合过程的能量分析表明，姜黄素的复合以加和的方式对姜黄素-Aβ原纤维的相互作用作出贡献。姜黄素与原纤维的结合是由姜黄素与原纤维之间的疏水相互作用、姜黄素的自聚集和溶剂化作用共同驱动的。这些相互作用可能在阻断 Aβ寡聚物毒性和诱导原纤维形成实验中观察到的“偏离途径”的蠕虫状纤维的生长方面起着关键作用。
