ABSTRACT Formation of insoluble toxic aggregates by hIAPP polypeptide is found to be a core component for disease pathogenicity of patients suffering from type II diabetes. Naturally occurring polyphenols that possess anti-aggregation property are being majorly studied in the current scenario for treating various conformational diseases. Herein, we study the disaggregation mechanism of naturally occurring polyphenol baicalein, obtained from the roots of S. baicalensis and Indian trumpet flower on hIAPP dimer using quantum chemical calculation and discrete molecular dynamics. Our study reported that a drastic loss in the secondary structural propensity of hIAPP was seen upon binding of baicalein. Notably, the hydrophobic core and the phenolic groups present in the ends of baicalein molecule play a key role in inhibiting the aggregates formed upon binding to the amyloidogenic core region of hIAPP. Thus, our study provides a comprehensive understanding over the disaggregation effect of baicalein on hIAPP dimer from a computational point of view and thereby bridging the gap for future therapeutic strategy in designing the anti-aggregation compounds that inhibit hIAPP amyloids.

中文翻译：

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分子力学和量子化学计算揭示黄芩素对人胰岛淀粉样多肽聚集体的抑制作用

摘要 hIAPP 多肽形成的不溶性毒性聚集体被认为是 II 型糖尿病患者疾病致病性的核心成分。在当前用于治疗各种构象疾病的情况下，正在主要研究具有抗聚集特性的天然多酚。在此，我们使用量子化学计算和离散分子动力学研究了从黄芩和印度喇叭花根中提取的天然多酚黄芩素在 hIAPP 二聚体上的分解机制。我们的研究报告说，与黄芩素结合后，hIAPP 的二级结构倾向急剧下降。尤其，存在于黄芩素分子末端的疏水核心和酚基在抑制与 hIAPP 的淀粉样蛋白生成核心区域结合后形成的聚集体方面发挥着关键作用。因此，我们的研究从计算的角度全面了解了黄芩素对 hIAPP 二聚体的分解作用，从而弥合了未来在设计抑制 hIAPP 淀粉样蛋白的抗聚集化合物方面的治疗策略的差距。