Amyloid formation of the human islet amyloid polypeptide (hIAPP) correlates with a loss of insulin-producing beta cells in patients with type II diabetes mellitus. In this study, we investigated the binding of hIAPP to bilayers consisting of ganglioside lipids and dioleoylphosphatidylcholine (DOPC), which is a physiologically relevant lipid species for pancreatic beta cell-associated aggregation. The membrane interactions are studied computationally using a combination of coarse-grained, umbrella sampling, and atomistic molecular dynamics simulations. Herein, we demonstrate how the hIAPP peptides accumulate in the areas with a high content of ganglioside lipids. We have characterized two distinct binding modes of hIAPP on ganglioside-rich membranes, with both binding modes formed due to electrostatic interaction between the cationic peptides and the anionic ganglioside headgroup. We observed that binding in the ganglioside headgroup region induced conformational changes of the peptide towards an aggregation prone conformation, rich in β-strands. In contrast, the binding of hIAPP near the ganglioside-enriched areas mobilizes the peptide, preventing it from conformational changes and potentially shields it from interactions with other peptides. This suggests a dual role of ganglioside lipids, affecting the aggregation of hIAPP by either accelerating or inhibiting amyloid formation depending on the membrane binding and the ganglioside concentration.

中文翻译：

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揭示神经节苷脂脂质在膜相关的胰岛淀粉样多肽聚集中的双重作用。

人胰岛淀粉样多肽（hIAPP）的淀粉样形成与II型糖尿病患者中胰岛素产生β细胞的丢失有关。在这项研究中，我们调查了hIAPP结合由神经节苷脂和二油酰磷脂酰胆碱（DOPC）组成的双层，这是与胰腺β细胞相关的聚集的生理相关脂质。通过结合使用粗颗粒，伞状采样和原子分子动力学模拟来计算研究膜相互作用。在本文中，我们证明了hIAPP肽如何在神经节苷脂脂质含量高的区域积聚。我们已经在富含神经节苷脂的膜上表征了hIAPP的两种不同结合模式，由于阳离子肽和阴离子神经节苷脂头基之间的静电相互作用而形成两种结合模式。我们观察到神经节苷脂头基区域中的结合诱导了肽的构象变化，向易于聚集的，富含β链的构象变化。相反，hIAPP在神经节苷脂富集区域附近的结合使肽动员，阻止其构象变化，并可能使其与其他肽的相互作用受到屏蔽。这表明神经节苷脂脂质的双重作用，取决于膜结合和神经节苷脂浓度，通过加速或抑制淀粉样蛋白形成而影响hIAPP的聚集。我们观察到神经节苷脂头基区域中的结合诱导了肽的构象变化，趋向于富含β链的易于聚集的构象。相反，hIAPP在神经节苷脂富集区域附近的结合使肽动员，阻止其构象变化，并可能使其与其他肽的相互作用受到屏蔽。这表明神经节苷脂脂质的双重作用，取决于膜结合和神经节苷脂浓度，通过加速或抑制淀粉样蛋白形成而影响hIAPP的聚集。我们观察到神经节苷脂头基区中的结合诱导了肽向富含β链的易于聚集的构象的构象变化。相反，hIAPP在神经节苷脂富集区域附近的结合使肽动员，阻止其构象变化，并可能使其与其他肽的相互作用受到屏蔽。这表明神经节苷脂脂质的双重作用，取决于膜结合和神经节苷脂浓度，通过加速或抑制淀粉样蛋白形成而影响hIAPP的聚集。