School of Pharmacy, Lanzhou University, Lanzhou, China.
School of Pharmacy, Lanzhou University, Lanzhou, China; State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.
PLoS One. 2014 Apr 16;9(4):e94796. doi: 10.1371/journal.pone.0094796. eCollection 2014.
EGCG possesses the ability of disaggregating the existing amyloid fibrils which were associated with many age-related degenerative diseases. However, the molecular mechanism of EGCG to disaggregate these fibrils is poorly known. In this work, to study the influence of EGCG on the full-length human islet amyloid polypeptide 1-37 (hIAPP1-37) oligomers, molecular dynamics simulations of hIAPP1-37 pentamer and decamer with EGCG were performed, respectively. The obtained results indicate that EGCG indeed destabilized the hIAPP1-37 oligomers. The nematic order parameter and secondary structure calculations coupled with the free-energy landscape indicate that EGCG broke the initial ordered pattern of two polymers, greatly reduced their β-sheet content and enlarged their conformational space. On this basis, three possible target sites were identified with the binding capacity order of S1>S2>S3. After a deeper analysis of each site, we found that S1 was the most possible site on which residues B-Ile26/Ala25, A-Phe23, B/C-Leu27 and E-Tyr37 played an important role for their binding. The proposal of this molecular mechanism can not only provide a prospective interaction figure between EGCG and β-sheet-rich fibrils of hIAPP1-37, but also is useful for further discovering other potential inhibitors.
EGCG 具有解聚与许多年龄相关退行性疾病相关的现有淀粉样纤维的能力。然而，EGCG 解聚这些纤维的分子机制知之甚少。在这项工作中，为了研究 EGCG 对全长人胰岛淀粉样多肽 1-37（hIAPP1-37）低聚物的影响，分别进行了含 EGCG 的 hIAPP1-37 五聚体和十聚体的分子动力学模拟。结果表明，EGCG 确实使 hIAPP1-37 低聚物不稳定。向列有序参数和二级结构计算以及自由能景观表明，EGCG 破坏了两个聚合物的初始有序模式，大大降低了它们的β-折叠含量并扩大了它们的构象空间。在此基础上，确定了三个可能的靶位，结合能力顺序为 S1>S2>S3。对每个位点进行更深入的分析后，我们发现 S1 是最有可能的位点，残基 B-Ile26/Ala25、A-Phe23、B/C-Leu27 和 E-Tyr37 对其结合具有重要作用。该分子机制的提出不仅可以提供 EGCG 与 hIAPP1-37 的富含β-折叠的纤维之间的有前景的相互作用图，而且对于进一步发现其他潜在抑制剂也很有用。
