Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, OH 44325, USA.
Biochemistry. 2013 Feb 12;52(6):1089-100. doi: 10.1021/bi301525e. Epub 2013 Jan 29.
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.
人胰岛淀粉样多肽（hIAPP 或胰岛淀粉样肽）是 2 型糖尿病患者胰腺淀粉样沉积物的致病因子。全长 hIAPP（1-37）聚集成小寡聚体物种，越来越被认为是导致细胞功能障碍和死亡的原因。然而，与 hIAPP 仅在 37 个残基中的 6 个残基不同的大鼠 IAPP（rIAPP（1-37））失去了形成毒性淀粉样物质的聚集能力。淀粉样多肽的结构和毒性的序列效应的原子细节，包括致淀粉样的、有毒的 hIAPP 肽和非淀粉样的、无毒的 rIAPP 肽之间的结构和毒性，仍然不清楚。在这里，我们使用分子动力学模拟研究了不同 hIAPP 和 rIAPP 多态形式从单体到五聚体的结构稳定性、构象动力学和驱动力之间的序列诱导差异。模拟表明，hIAPP 从三聚体到五聚体形成具有高度结构稳定性，保留了良好的对齐平行β-折叠和 U 型构象。hIAPP 三聚体似乎是溶液中的最小最小种子。平行 hIAPP 低聚物的稳定性随着肽的数量增加而增加。相反，用 rIAPP 序列替代 hIAPP 序列会导致所有 rIAPP 低聚物中肽间相互作用的显著丧失，从而破坏 C 末端β-折叠、转弯构象和整体稳定性。较少的β-折叠丰富结构和紊乱的 U 型拓扑结构对 rIAPP 肽自组装成高度有序、对齐的β-折叠丰富原纤维和纤维施加了很大的能量惩罚，这解释了 rIAPP 的非淀粉样活性。此外，在包装良好的高阶 hIAPP 低聚物中，而不是在包装不良的 rIAPP 低聚物中，U 型转弯区域内没有内部水，这也稳定了肽的缔合。这项工作提供了致淀粉样的 hIAPP 与其类似物（如非淀粉样的 rIAPP 和一些突变体）之间的序列-结构关系的原子细节，这有助于开发新型治疗剂来阻止毒性 hIAPP 寡聚体的形成，从而治疗 2 型糖尿病。
