Molecular Mechanism of the Inhibition and Remodeling of Human Islet Amyloid Polypeptide (hIAPP1鈥?7) Oligomer by Resveratrol from Molecular Dynamics Simulation

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• 作者：Qianqian Wang ; Lulu Ning ; Yuzhen Niu ; Huanxiang Liu ; Xiaojun Yao
• 刊名：Journal of Physical Chemistry B
• 出版年：2015
• 出版时间：January 8, 2015
• 年：2015
• 卷：119
• 期：1
• 页码：15-24
• 全文大小：575K
• ISSN：1520-5207

文摘

Natural polyphenols are one of the most actively investigated categories of amyloid inhibitors, and resveratrol has recently been reported to inhibit and remodel the human islet amyloid polypeptide (hIAPP) oligomers and fibrils. However, the exact mechanism of its action is still unknown, especially for the full-length hIAPP_1鈥?7. To this end, we performed all-atom molecular dynamics simulations for hIAPP_1鈥?7 pentamer with and without resveratrol. The obtained results show that the binding of resveratrol is able to cause remarkable conformational changes of hIAPP_1鈥?7 pentamer, in terms of secondary structures, order degree, and morphology. By clustering analysis, two possible binding sites of resveratrol on the hIAPP_1鈥?7 pentamer were found, located at the grooves of the top and bottom surfaces of 尾-sheet layer, respectively. After the binding free energy calculation and residue energy decomposition, it can be concluded that the bottom site is the more possible one, and that the nonpolar interactions act as the driving force for the binding of hIAPP_1鈥?7 to resveratrol. In addition, Arg11 is the most important residue for the binding of resveratrol. The full understanding of inhibitory mechanism of resveratrol on the hIAPP_1鈥?7 oligomer, and the identification of its binding sites on this protein are helpful for the future design and discovery of new amyloid inhibitors.