Wang Qianqian, Zhou Shuangyan, Wei Wei, Yao Xiaojun, Liu Huanxiang, Hu Zhide
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
Phys Chem Chem Phys. 2015 Nov 21;17(43):29103-12. doi: 10.1039/c5cp03991f.
The aggregation of human islet amyloid polypeptide (hIAPP) is closely related with the occurrence of type 2 diabetes (T2D). Natural flavonoid morin was confirmed to not only inhibit the amyloid formation of hIAPP, but disaggregate its preformed amyloid fibrils. In this study, with the goal of elucidating the molecular mechanism of inhibition and destabilization of morin on the full-length hIAPP(1-37) oligomer, molecular dynamics simulations were performed for hIAPP(1-37) pentamer in the presence and absence of morin. The obtained results show that during the protein-inhibitor interaction, morin can notably alter the structural properties of hIAPP(1-37) pentamer, such as morphology, solvent accessible surface area and secondary structure. Moreover, we identified three possible binding sites of morin on hIAPP, all of which located near the amyloidogenic region of this protein. From the binding free energy calculations, we found that Site II was the most possible one. Further conformational analysis together with energy decomposition showed that the residues His18, Phe23 and Ile26 play a key role in the binding with morin by hydrogen bond, π-π and hydrophobic interactions. The proposal of the theoretical mechanism of morin against hIAPP aggregation will provide valuable information for the development of new drugs to inhibit hIAPP aggregation.
人胰岛淀粉样多肽（hIAPP）的聚集与2型糖尿病（T2D）的发生密切相关。天然黄酮类化合物桑色素不仅能抑制hIAPP的淀粉样形成，还能使其预先形成的淀粉样纤维解聚。在本研究中，为了阐明桑色素对全长hIAPP(1-37)寡聚体抑制和去稳定作用的分子机制，对存在和不存在桑色素的hIAPP(1-37)五聚体进行了分子动力学模拟。所得结果表明，在蛋白质-抑制剂相互作用过程中，桑色素能显著改变hIAPP(1-37)五聚体的结构性质，如形态、溶剂可及表面积和二级结构。此外，我们确定了桑色素在hIAPP上的三个可能结合位点，它们均位于该蛋白的淀粉样生成区域附近。通过结合自由能计算，我们发现位点II是最有可能的结合位点。进一步的构象分析和能量分解表明，His18、Phe23和Ile26残基通过氢键、π-π和疏水相互作用在与桑色素的结合中起关键作用。桑色素对抗hIAPP聚集的理论机制的提出将为开发抑制hIAPP聚集的新药提供有价值的信息。
