Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, PC and PS lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity is found to correlate with the insertion depth of IAPP, which is found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.

中文翻译：

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胆固醇对膜结合胰岛淀粉样多肽的影响


胰岛淀粉样多肽 (IAPP) 被认为是 II 型糖尿病患者 β 细胞质量减少的原因。细胞膜的分子组成对于调节 IAPP 细胞毒性和聚集很重要。胆固醇在胰腺 β 细胞中以高浓度存在，体外实验表明，它通过直接相互作用或改变膜的性质来影响 IAPP 淀粉样蛋白的形成。在这项研究中，我们应用微秒时间尺度的原子、无偏分子动力学模拟来研究胆固醇对膜结合 IAPP 的影响。使用胆固醇、PC 和 PS 脂质的各种组合进行模拟。在所有模拟中，单体 IAPP 的螺旋结构均由膜稳定。我们发现，与纯磷脂膜相比，胆固醇降低了 IAPP 的插入深度，而 PS 脂质则抵消了胆固醇的影响。研究发现聚集倾向与 IAPP 的插入深度相关，随着胆固醇诱导的脂质有序性的增加，IAPP 的插入深度会降低。 IAPP 附近的胆固醇被耗尽，因此我们的结果表明胆固醇的影响是间接的。