State Key Laboratory of Surface Physics, Key Laboratory for Computational Physical Sciences (MOE), and Department of Physics, Fudan University , 220 Handan Road, Shanghai 200433, China.
Collaborative Innovation Center of Advanced Microstructures , Nanjing 210093, China.
J Phys Chem B. 2017 Oct 5;121(39):9203-9212. doi: 10.1021/acs.jpcb.7b08652. Epub 2017 Sep 22.
The accumulation of the human islet amyloid polypeptide (hIAPP) deposits in the pancreas is regarded as an important factor that leads to the depletion of islet β-cells and islet transplantation failure. In recent experiments, it was reported that a small organic molecule O4 inhibits the formation of hIAPP1-37 oligomers and fibrils. However, the interaction between O4 molecules and hIAPP oligomers is largely unknown on the atomic level. In this work, we studied the influence of O4 molecules on fibril-like hIAPP pentamer and decamer by performing atomistic molecular dynamics simulations. Our results show that O4 molecules mostly bind to the amyloid core region spanning residues 22NFGAI26 for both hIAPP pentamer and decamer, which leads to the local disruption of interpeptide β-sheets. The calculation of contact probability and binding energy indicates that the binding of O4 molecules is mostly driven by aromatic stacking and hydrophobic interactions. Our work reveals the detailed disruption mechanism of full-length hIAPP protofibrils by O4 molecules and may be helpful to the design of more efficient inhibitors against hIAPP aggregation.
人胰岛淀粉样多肽（hIAPP）在胰腺中的积累被认为是导致胰岛β细胞耗竭和胰岛移植失败的重要因素。在最近的实验中，有报道称小分子有机化合物 O4 可以抑制 hIAPP1-37 寡聚物和纤维的形成。然而，O4 分子与 hIAPP 寡聚物之间的相互作用在原子水平上在很大程度上是未知的。在这项工作中，我们通过进行原子分子动力学模拟研究了 O4 分子对纤维状 hIAPP 五聚体和十聚体的影响。研究结果表明，对于 hIAPP 五聚体和十聚体，O4 分子主要结合在残基 22NFGAI26 跨越的淀粉样核心区域，导致肽间β-片层的局部破坏。接触概率和结合能的计算表明，O4 分子的结合主要是由芳构堆积和疏水相互作用驱动的。我们的工作揭示了 O4 分子对全长 hIAPP 原纤维的详细破坏机制，这可能有助于设计更有效的 hIAPP 聚集抑制剂。
