Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
Biochim Biophys Acta Mol Basis Dis. 2019 Feb 1;1865(2):434-444. doi: 10.1016/j.bbadis.2018.11.021. Epub 2018 Nov 28.
The self-assembly of human islet amyloid polypeptide (hIAPP) into β-sheet rich amyloid aggregates is associated with pancreatic β-cell death in type 2 diabetes (T2D). Prior experimental studies of hIAPP aggregation reported the early accumulation of α-helical intermediates before the rapid conversion into β-sheet rich amyloid fibrils, as also corroborated by our experimental characterizations with transmission electron microscopy and Fourier transform infrared spectroscopy. Although increasing evidence suggests that small oligomers populating early hIAPP aggregation play crucial roles in cytotoxicity, structures of these oligomer intermediates and their conformational conversions remain unknown, hindering our understanding of T2D disease mechanism and therapeutic design targeting these early aggregation species. We further applied large-scale discrete molecule dynamics simulations to investigate the oligomerization of full-length hIAPP, employing multiple molecular systems of increasing number of peptides. We found that the oligomerization process was dynamic, involving frequent inter-oligomeric exchanges. On average, oligomers had more α-helices than β-sheets, consistent with ensemble-based experimental measurements. However, in ~4-6% independent simulations, β-rich oligomers expected as the fibrillization intermediates were observed, especially in the pentamer and hexamer simulations. These β-rich oligomers could adopt β-barrel conformations, recently postulated to be the toxic oligomer species but only observed computationally in the aggregates of short amyloid protein fragments. Free-energy analysis revealed high energies of these β-rich oligomers, supporting the nucleated conformational changes of oligomers in amyloid aggregation. β-barrel oligomers of full-length hIAPP with well-defined three-dimensional structures may play an important pathological role in T2D etiology and may be a therapeutic target for the disease.
人胰岛淀粉样多肽（hIAPP）自组装成富含β-折叠的淀粉样纤维与 2 型糖尿病（T2D）中的胰腺β细胞死亡有关。先前关于 hIAPP 聚集的实验研究报告称，在快速转化为富含β-折叠的淀粉样纤维之前，会早期积累α-螺旋中间体，这也得到了我们用透射电子显微镜和傅里叶变换红外光谱进行的实验特征的证实。尽管越来越多的证据表明，早期 hIAPP 聚集中富含的小寡聚体在细胞毒性中起着至关重要的作用，但这些寡聚体中间体的结构及其构象转化仍然未知，这阻碍了我们对 T2D 发病机制的理解和针对这些早期聚集物的治疗设计。我们进一步应用大规模离散分子动力学模拟来研究全长 hIAPP 的寡聚化，使用多个分子系统，其中包含数量不断增加的肽。我们发现寡聚化过程是动态的，涉及频繁的寡聚体间交换。平均而言，寡聚体比β-折叠具有更多的α-螺旋，与基于集合的实验测量结果一致。然而，在大约 4-6%的独立模拟中，观察到了预期作为纤维化中间体的富含β的寡聚体，尤其是在五聚体和六聚体模拟中。这些富含β的寡聚体可以采取β-桶构象，最近被认为是毒性寡聚体物种，但仅在短淀粉样蛋白片段的聚集体中计算观察到。自由能分析显示这些富含β的寡聚体具有很高的能量，支持寡聚体在淀粉样聚集中的核构象变化。具有明确三维结构的全长 hIAPP 的β-桶寡聚体可能在 T2D 的发病机制中发挥重要的病理作用，并且可能成为该疾病的治疗靶点。
