Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co‐secreted with insulin from β cells of the pancreas. In patients suffering from type‐2 diabetes, amylin self‐assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi‐pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 1:1 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre‐treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre‐formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 μs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.

中文翻译：

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基于 MD 数据和实验验证的马尔可夫状态模型揭示了基于天然化合物白花丹素的 hIAPP 抑制作用

人胰岛淀粉样多肽（胰岛淀粉样多肽或 hIAPP）是一种 37 残基激素，与胰腺 β 细胞的胰岛素共同分泌。在患有 2 型糖尿病的患者中，胰淀素会自组装成淀粉样原纤维，最终导致胰腺细胞死亡。然而，在预防和治疗此类淀粉样变性方面存在研究空白。白花丹素是一种天然化合物，此前已被证明具有抑制胰岛素淀粉样变性的潜力。我们的研究揭示了 hIAPP 内的可塌陷区域，塌陷后会促进疏水性和 pi-pi 相互作用，最终导致聚集。有趣的是，白花丹素表现出结合这些特定可折叠区域的能力，从而阻止上述相互作用，否则会驱动 hIAPP 聚集。我们使用原子分子动力学方法来确定二级结构变化。 MSM 显示在 PGN 存在下形成类似 hIAPP 结构的亚稳态。我们的计算机结果与体外结果一致。 ThT 测定显示，hIAPP 与 Plumbagin 的比例为 1:1 时，荧光强度显着降低 50%。这一发现表明白花丹素可显着抑制淀粉样原纤维的形成，因为 ThT 荧光与这些原纤维的存在直接相关。进一步的 TEM 图像显示白花丹素预处理的 hIAPP 样品中 hIAPP 原纤维消失。此外，我们还发现，白花丹素会破坏 hIAPP 原纤维中的分子间氢键，导致平均 β 链间距增加，从而导致预形成原纤维解聚，从而证明 hIAPP 聚集机制的整体破坏。我们的工作是第一个报告 hIAPP 22 μs 详细原子模拟的工作。总体而言，我们的研究将白花丹素视为 hIAPP 淀粉样变性预防和治疗的潜在候选者。