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首页> 外文期刊>Biochemistry >Comparative molecular dynamics study of human islet amyloid polypeptide (IAPP) and Rat IAPP oligomers
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Comparative molecular dynamics study of human islet amyloid polypeptide (IAPP) and Rat IAPP oligomers

机译：人胰岛淀粉样多肽（IAPP）和大鼠IAPP寡聚物的分子动力学比较研究

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Human islet amyloid polypeptide (hIAPP or amylin) is a causative agent in pancreatic amyloid deposits found in patients with type 2 diabetes. The aggregation of full-length hIAPP_(1-37) into small oligomeric species is increasingly believed to be responsible for cell dysfunction and death. However, rat IAPP (rIAPP_(1-37)), which differs from hIAPP in only six of 37 residues, loses its aggregation ability to form toxic amyloid species. Atomic details of the effect of sequence on the structure and toxicity between the amyloidogenic, toxic hIAPP peptide and the nonamyloidogenic, nontoxic rIAPP peptide remain unclear. Here, we probe sequence-induced differences in structural stability, conformational dynamics, and driving forces between different hIAPP and rIAPP polymorphic forms from monomer to pentamer using molecular dynamics simulations. Simulations show that hIAPP forms from trimer to pentamer exhibit high structural stability with well-preserved in-register parallel β-sheet and the U-bend conformation. The hIAPP trimer appears to be a smallest minimal seed in solution. The stabilities of parallel hIAPP oligomers increase with the number of peptides. Conversely, replacement of hIAPP sequence by rIAPP sequence causes a significant loss of favorable interpeptide interactions in all rIAPP oligomers, destabilizing the C-terminal β-sheet, turn conformation, and overall stability. A less β-sheet-rich structure and a disturbed U-shaped topology exert a large energy penalty on the self-assemble of the rIAPP peptides into highly ordered, in-register β-sheet-rich protofibrils and fibrils, which explains the nonamyloidogenic activity of rIAPP. Moreover, the absence of interior water within the U-turn region in the well-packed higher-order hIAPP oligomers, not in the poorly packed rIAPP oligomers, also stabilizes peptide association. This work provides atomic details of the sequence-structure relationship between the amyloidogenic hIAPP and its analogues such as the nonamyloidogenic rIAPP and some mutants, which could help in the development of novel therapeutic agents to block the formation of toxic hIAPP oligomeric species for type 2 diabetes.
机译：人胰岛淀粉样蛋白多肽（hIAPP或淀粉样蛋白）是2型糖尿病患者胰腺淀粉样蛋白沉积物的病原体。人们越来越相信全长hIAPP_（1-37）会聚集成小的寡聚物种，这是造成细胞功能障碍和死亡的原因。但是，大鼠IAPP（rIAPP_（1-37））与hIAPP的区别仅在于37个残基中的六个残基，它失去了形成有毒淀粉样物质的聚集能力。尚不清楚序列对产生淀粉样的，有毒的hIAPP肽与非淀粉样的，无毒的rIAPP肽之间的结构和毒性的影响的原子细节。在这里，我们使用分子动力学模拟研究了从单体到五聚体的不同hIAPP和rIAPP多晶型形式之间序列诱导的结构稳定性，构象动力学和驱动力的差异。模拟表明，从三聚体到五聚体的hIAPP形式均显示出高结构稳定性，并具有良好保存的配准平行β-折叠和U形弯曲构象。 hIAPP三聚体似乎是溶液中最小的最小种子。平行的hIAPP寡聚物的稳定性随肽的数量而增加。相反，用rIAPP序列替换hIAPP序列会导致所有rIAPP寡聚体中有利的肽间相互作用显着丧失，从而破坏C端β-sheet的稳定性，转向构象和总体稳定性。较少的富含β-折叠的结构和受干扰的U形拓扑结构对rIAPP肽的自组装成高度有序的，富含β-折叠的原纤维和原纤维的自组装产生了巨大的能量损失，这说明了非淀粉样生成活性rIAPP。此外，在堆积良好的高阶hIAPP寡聚体中，而不是在堆积不良的rIAPP寡聚体中，在掉头区域内不存在内部水，这也使肽缔合稳定。这项工作提供了产生淀粉样蛋白的hIAPP及其类似物（非淀粉样蛋白的rIAPP和某些突变体）之间的序列-结构关系的原子细节，这可能有助于开发新型治疗剂，以阻止2型糖尿病的有毒hIAPP寡聚物种的形成。 。

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