Dong Mingyan, Zhao Wei, Hu Dingkun, Ai Hongqi, Kang Baotao
Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School of Chemistry and Chemical Engineering, University of Jinan , Jinan 250022, China.
ACS Chem Neurosci. 2017 Jul 19;8(7):1577-1588. doi: 10.1021/acschemneuro.7b00080. Epub 2017 Apr 28.
Amyloid-β (Aβ/Aβ) peptide with a length of 40 or 42 residues is naturally secreted as cleavage product of the amyloid precursor protein, and formation of Aβ aggregates in a patient's brain is a hallmark of Alzheimer's disease (AD). Therefore, disaggregation and disruption provide potential therapeutic approaches to reduce, inhibit, and even reverse Aβ aggregation. The disaggregation/inhibition effect of the inhibitors applies generally to both Aβ and Aβ aggregations. Here we capture the atomic-level details of the interaction between Aβ/Aβ and either natural tanshinone compound TS1 or its derivative TS0, and observe novel results by using molecular dynamics simulations. We observe that the natural TS1 indeed inhibits the monomolecular Aβ (mAβ) aggregation and disaggregates Aβ amyloid fibrils, being in good agreement with the experimental results. TS1 is favorable to stabilize mAβ and even Aβ fibril, playing an opposite role to that in the Aβ counterpart, however. TS0 can inhibit the misfolding of either mAβ or mAβ and disaggregate Aβ fibril but stabilize the Aβ fibril. Using a combination of secondary structural analysis, MM-PBSA binding energy calculations, and radial distribution functions computations, we find that both TS0 and TS1, especially the former, prefer to bind at the charged residues within disordered N-terminus with a scarce positive binding energy and disappear the characteristic C-terminal bend region of Aβ fibril, as well as twist the Aβ fibril seriously. It turns out to destabilize the Aβ fibril and enable the conversion of U-shaped Aβ fibril from the onefold to the twofold morphologies. The N-terminal binding preference helps us to identify N-terminal region as the specific epitope for specific inhibitors/drugs (such as TS0 and analogues), heralding unusual inhibition/disaggregation or stabilization mechanisms, and offering an alternative direction in engineering new inhibitors to treat AD.
长度为40或42个残基的淀粉样β肽（Aβ/Aβ）是淀粉样前体蛋白的裂解产物，会自然分泌，而患者大脑中Aβ聚集体的形成是阿尔茨海默病（AD）的一个标志。因此，解聚和破坏为减少、抑制甚至逆转Aβ聚集提供了潜在的治疗方法。抑制剂的解聚/抑制作用通常适用于Aβ和Aβ聚集体。在此，我们捕捉了Aβ/Aβ与天然丹参酮化合物TS1或其衍生物TS0之间相互作用的原子水平细节，并通过分子动力学模拟观察到了新的结果。我们观察到天然TS1确实抑制单分子Aβ（mAβ）聚集并使Aβ淀粉样纤维解聚，这与实验结果高度一致。然而，TS1有利于稳定mAβ甚至Aβ纤维，这与Aβ对应物中的作用相反。TS0可以抑制mAβ或mAβ的错误折叠并使Aβ纤维解聚，但会稳定Aβ纤维。通过结合二级结构分析、MM-PBSA结合能计算和径向分布函数计算，我们发现TS0和TS1，尤其是前者，更倾向于结合在无序N端的带电残基上，结合能为稀缺的正值，并使Aβ纤维的特征性C端弯曲区域消失，同时严重扭曲Aβ纤维。结果表明，这会使Aβ纤维不稳定，并使U形Aβ纤维从单重形态转变为双重形态。N端结合偏好帮助我们将N端区域确定为特定抑制剂/药物（如TS0及其类似物）的特定表位，预示着不同寻常的抑制/解聚或稳定机制，并为设计治疗AD的新抑制剂提供了一个替代方向。
