Abstract：
Amyloid-beta (Aβ) protofibrils are closely related to Alzheimer\'s disease. Their behaviors with or without the presence of Aβ fibrillization inhibitors have been intensively studied by molecular dynamics simulations. In this work, the molecular mechanisms of licochalcone A and licochalcone B on destabilizing Aβ(1-42) protofibrils are explored. It is found that both two licochalcones can disorder the configuration of the Aβ(1-42) protofibril. The stable interactions between the Aβ(1-42) protofibril and licochalcone A or licochalcone B are able to be formed. A reduction of the β-sheet structure contents and an increment of the random coil structures of Aβ(1-42) protofibril are observed in the presence of either licochalcone A or licochalcone B. The hydrogen bonds inside the Aβ(1-42) protofibril could be partially collapsed to varying degrees by two licochalcones. Furthermore, the van der Waals interactions between Aβ(1-42) protofibril and licochalcone A make an important contribution to the binding free energy, while the contribution of the electrostatic interactions between Aβ(1-42) protofibril and licochalcone B is more prominent in the binding affinity. Our work may help in the development of new drug candidates for disrupting the Aβ protofibril.
摘要：
β淀粉样蛋白(Aβ)原纤维与阿尔茨海默病密切相关。在存在或不存在Aβ纤维化抑制剂的情况下，它们的行为已通过分子动力学模拟进行了深入研究。在这项工作中,探讨了甘草查尔酮A和甘草查尔酮B对Aβ（1-42）原纤维不稳定的分子机制。发现两种甘草茶碱都可以使Aβ（1-42）原原纤维的构型紊乱。能够形成Aβ（1-42）原原纤维与氯查尔酮A或氯查尔酮B之间的稳定相互作用。在存在LogochalconeA或LogochalconeB的情况下，观察到Aβ（1-42）原原纤维的β-折叠结构含量的降低和无规卷曲结构的增加。此外，Aβ(1-42)原纤与甘草查尔酮A的范德华相互作用对结合自由能有重要贡献,而Aβ（1-42）原原纤维与甘草查尔酮B之间的静电相互作用在结合亲和力中的贡献更为突出。我们的工作可能有助于开发破坏Aβ原原纤维的新药。
