Exploring the influence of EGCG on the β-sheet-rich oligomers of human islet amyloid polypeptide (hIAPP1-37) and identifying its possible binding sites from molecular dynamics simulation.
Exploring the influence of EGCG on the β-sheet-rich oligomers of human islet amyloid polypeptide (hIAPP1-37) and identifying its possible binding sites from molecular dynamics simulation.
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探索 EGCG 对人胰岛淀粉样多肽 (hIAPP(1-37)) 富含 β-折叠寡聚物的影响并通过分子动力学模拟鉴定其可能的结合位点
DOI：
10.1371/journal.pone.0094796
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yao X
中科院分区：
文献类型：
--
作者：
Wang Q;Guo J;Jiao P;Liu H;Yao X
表没食子儿茶素没食子酸酯具有解聚淀粉样纤维的能力，淀粉样纤维与许多与年龄相关的退行性疾病有关。然而，EGCG解聚这些纤维的分子机制知之甚少。为了研究表没食子儿茶素没食子酸酯（EGCG）对人胰岛淀粉样多肽1-37（hIAPP 1 -37）寡聚体的影响，分别对hIAPP 1 -37五聚体和十聚体与EGCG的相互作用进行了分子动力学模拟。所获得的结果表明，EGCG确实使hIAPP 1 -37寡聚体不稳定。结合自由能谱和二级结构计算表明，EGCG打破了两种聚合物的初始有序结构，大大减少了它们的β-折叠含量，扩大了它们的构象空间。在此基础上，确定了3个可能的靶位点，结合能力顺序为S1>S2>S3。通过对各位点的深入分析，发现S1是最有可能的位点，残基B-Ile 26/Ala 25，A-Phe 23，B/C-Leu 27和E-Tyr 37在其上发挥重要作用。这一分子机制的提出不仅为进一步研究EGCG与hIAPP 1 -37的β-折叠纤维的相互作用提供了理论依据，也为进一步发现其他潜在的抑制剂奠定了基础。
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.
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DOI：
10.1016/j.bbrc.2010.08.088
发表时间：
2010-10-01
影响因子：
3.1
作者：
Bae, Song Yi;Kim, Seulgi;Kim, T. Doohun
通讯作者：
Kim, T. Doohun
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P
影响因子：
4.1
作者：
Kalé, L;Skeel, R;Schulten, K
通讯作者：
Schulten, K
影响因子：
18.3
作者：
Brender, Jeffrey R.;Salamekh, Samer;Ramamoorthy, Ayyalusamy
通讯作者：
Ramamoorthy, Ayyalusamy
影响因子：
3.7
作者：
Guo J;Li J;Zhang Y;Jin X;Liu H;Yao X
通讯作者：
Yao X