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.

中文翻译：

---

Orcein相关的小分子O4主要通过与淀粉样蛋白生成的核心区域相互作用，从而使hIAPP原纤维不稳定。

人胰岛淀粉样多肽（hIAPP）沉积物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，据报道，小的有机分子O4抑制了hIAPP1-37低聚物和原纤维的形成。但是，在原子水平上，O4分子与hIAPP低聚物之间的相互作用尚不清楚。在这项工作中，我们通过执行原子分子动力学模拟研究了O4分子对原纤维样hIAPP五聚体和十聚体的影响。我们的研究结果表明，O4分子大多数与跨过hIAPP五聚体和decamer残基22NFGAI26的淀粉样蛋白核心区域结合，这导致了肽间β-折叠的局部破坏。接触概率和结合能的计算表明，O4分子的结合主要由芳族堆积和疏水相互作用驱动。我们的工作揭示了O4分子破坏全长hIAPP原纤维的详细机制，可能有助于设计更有效的hIAPP聚集抑制剂。