School of Physics, Georgia Institute of Technology, Atlanta, Georgia; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia.
Biospectroscopy, Center for Protein Diagnostics, Ruhr University Bochum, Bochum, Germany; Department of Biophysics, Ruhr University Bochum, Bochum, Germany.
Biophys J. 2020 Jul 21;119(2):349-359. doi: 10.1016/j.bpj.2020.05.033. Epub 2020 Jun 10.
Amyloid-β (Aβ) is a macromolecular structure of great interest because its misfolding and aggregation, along with changes in the secondary structure, have been correlated with its toxicity in various neurodegenerative diseases. Small drug-like molecules can modulate the amyloid secondary structure and therefore have raised significant interest in applications to active and passive therapies targeting amyloids. In this study, we investigate the interactions of epigallocatechin-3-gallate (EGCG), found in green tea, with Aβ polypeptides, using a combination of in vitro immuno-infrared sensor measurements, docking, molecular dynamics simulations, and ab initio calculations. We find that the interactions of EGCG are dominated by only a few residues in the fibrils, including hydrophobic π-π interactions with aromatic rings of side chains and hydrophilic interactions with the backbone of Aβ, as confirmed by extended (1-μs-long) molecular dynamics simulations. Immuno-infrared sensor data are consistent with degradation of Aβ fibril induced by EGCG and inhibition of Aβ fibril and oligomer formation, as manifested by the recovery of the amide-I band of monomeric Aβ, which is red-shifted by 26 cm when compared to the amide-I band of the fibrillar form. The shift is rationalized by computations of the infrared spectra of Aβ42 model structures, suggesting that the conformational change involves interchain hydrogen bonds in the amyloid fibrils that are broken upon binding of EGCG.
淀粉样蛋白-β（Aβ）是一种具有重要研究意义的大分子结构，因为其错误折叠和聚集，以及二级结构的变化，与各种神经退行性疾病中的毒性有关。小分子药物样分子可以调节淀粉样蛋白的二级结构，因此在针对淀粉样蛋白的主动和被动治疗的应用中引起了极大的兴趣。在这项研究中，我们使用体外免疫红外传感器测量、对接、分子动力学模拟和从头算计算相结合的方法，研究了绿茶中发现的表没食子儿茶素没食子酸酯（EGCG）与 Aβ 多肽的相互作用。我们发现，EGCG 的相互作用仅由纤维中的少数几个残基主导，包括与侧链芳香环的疏水 π-π 相互作用和与 Aβ 骨架的亲水性相互作用，这通过扩展（1-μs 长）分子动力学模拟得到了证实。免疫红外传感器数据与 EGCG 诱导的 Aβ 纤维降解以及抑制 Aβ 纤维和寡聚物形成一致，这表现为单体 Aβ 的酰胺-I 带恢复，与纤维形式的酰胺-I 带相比，红移了 26cm。通过对 Aβ42 模型结构的红外光谱计算，这一移位得到了合理化，表明构象变化涉及淀粉样纤维中的链间氢键，而氢键在 EGCG 结合时被打破。
