Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
J Phys Chem B. 2011 Oct 20;115(41):11879-87. doi: 10.1021/jp202640b. Epub 2011 Sep 23.
Considerable experimental evidence indicates that (-)-epigallocatechin-3-gallate (EGCG) inhibits the fibrillogenesis of Aβ(42) and alleviates its associated cytotoxicity. However, the molecular mechanism of the inhibition effect of EGCG on the conformational transition of Aβ(42) remains unclear due to the limitations of current experimental techniques. In this work, molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) analysis were coupled to better understand the issue. It was found that the direct interactions between EGCG and the peptide are the origin of its inhibition effects. Specifically, EGCG molecules expel water from the surface of the Aβ(42), cluster with each other, and interact directly with the peptide. The results of free energy decomposition calculated by MM-PBSA indicate that the nonpolar term contributes more than 71% to the binding free energy of the EGCG-Aβ(42) complex, while polar interactions (i.e., hydrogen bonding) play a minor role. It was identified that there are 12 important residues of Aβ(42) that strongly interact with EGCG (Phe4, Arg5, Phe19, Phe20, Glu22, Lys28, Gly29, Leu34-Gly37, and Ile41), while nonpolar interactions are mainly provided by the side chains of some hydrophobic residues (Phe, Met and Ile) and the main chains of some nonhydrophobic residues (Lys28 and Gly29). On the contrary, polar interactions are mainly formed by the main chain of Aβ(42), of which the main chains of Gly29 and Gly37 contribute greatly. The work has thus elucidated the molecular mechanism of the inhibition effect of EGCG on the conformational transition of Aβ(42), and the findings are considered critical for exploring more effective agents for the inhibition of Aβ(42) fibrillogenesis.
大量实验证据表明，(-)-表没食子儿茶素没食子酸酯（EGCG）可抑制 Aβ(42)的纤维形成并减轻其相关的细胞毒性。然而，由于目前实验技术的限制，EGCG 对 Aβ(42)构象转变抑制作用的分子机制仍不清楚。在这项工作中，我们将分子动力学模拟和分子力学-泊松-玻尔兹曼表面面积（MM-PBSA）分析相结合，以更好地理解这一问题。结果发现，EGCG 与肽之间的直接相互作用是其抑制作用的起源。具体而言，EGCG 分子将水从 Aβ(42)表面排挤出去，彼此聚集，并与肽直接相互作用。通过 MM-PBSA 计算的自由能分解结果表明，非极性项对 EGCG-Aβ(42)复合物结合自由能的贡献超过 71%，而极性相互作用（即氢键）的作用较小。确定了 Aβ(42)中有 12 个重要残基与 EGCG 强烈相互作用（Phe4、Arg5、Phe19、Phe20、Glu22、Lys28、Gly29、Leu34-Gly37 和 Ile41），而非极性相互作用主要由一些疏水性残基（Phe、Met 和 Ile）的侧链和一些非疏水性残基（Lys28 和 Gly29）的主链提供。相反，极性相互作用主要由 Aβ(42)的主链形成，其中 Gly29 和 Gly37 的主链贡献很大。因此，该研究阐明了 EGCG 抑制 Aβ(42)构象转变的分子机制，为探索更有效的抑制 Aβ(42)纤维形成的药物提供了重要依据。
