Molecular Insight into Conformational Transition of Amyloid 尾-Peptide 42 Inhibited by (鈭?-Epigallocatechin-3-gallate Probed by Molecular Simulations

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• 作者：Fu-Feng Liu ; Xiao-Yan Dong ; Lizhong He ; Anton P. J. Middelberg ; Yan Sun
• 刊名：Journal of Physical Chemistry B
• 出版年：2011
• 出版时间：October 20, 2011
• 年：2011
• 卷：115
• 期：41
• 页码：11879-11887
• 全文大小：1064K
• 年卷期：v.115,no.41(October 20, 2011)
• ISSN：1520-5207

文摘

Considerable experimental evidence indicates that (鈭?-epigallocatechin-3-gallate (EGCG) inhibits the fibrillogenesis of A尾₄₂ and alleviates its associated cytotoxicity. However, the molecular mechanism of the inhibition effect of EGCG on the conformational transition of A尾₄₂ remains unclear due to the limitations of current experimental techniques. In this work, molecular dynamics simulations and molecular mechanics-Poisson鈥揃oltzmann 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 A尾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-A尾₄₂ complex, while polar interactions (i.e., hydrogen bonding) play a minor role. It was identified that there are 12 important residues of A尾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 A尾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 A尾₄₂, and the findings are considered critical for exploring more effective agents for the inhibition of A尾₄₂ fibrillogenesis.