Département de Physique and Groupe de Recherche sur les Protéines Membranaires (GEPROM), Université de Montréal, Montréal, Québec, Canada.
J Phys Chem B. 2011 Mar 31;115(12):3146-54. doi: 10.1021/jp108870q. Epub 2011 Mar 8.
The loss of the insulin-producing β-cells in the pancreatic islets of Langerhans, responsible for type-II diabetes, is associated with islet amyloid deposits. The main component of these deposits is the amyloid fibrils formed by the 37-residue human islet amyloid polypeptide (hIAPP also known as amylin). Although the fibrils are well characterized by cross β structure, the structure of the transient oligomers formed in the early stage of aggregation remains elusive. In this study, we apply the Hamiltonian-temperature replica exchange molecular dynamics to characterize the structure and thermodynamics of a full-length hIAPP dimer in both the presence and the absence of the Cys2-Cys7 disulfide bond. We compare these results with those obtained on the monomeric and dimeric forms of rat IAPP (rIAPP) with a disulfide bridge which differ from the hIAPP by 6 amino acids in the C-terminal region, but it is unable to form fibrils. Using a coarse-grained protein force field (OPEP-the Optimized Potential for Efficient peptide structure Prediction) running for a total of 10-28 μs per system studied, we show that sequences sample α-helical structure in the N-terminal region but that the length of this secondary element is shorter and less stable for the chains without the disulfide bridge (residues 5-16 for hIAPP with the bridge vs 10-16 for hIAPP without the bridge). This α-helix is known to be an important transient stage in the formation of oligomers. In the C-terminal, the amyloidogenic region of hIAPP, β-strands are seen for residues 17-26 and 30-35. On the contrary, no significant β-sheet content in the C-terminal is observed for either the monomeric or the dimeric rIAPP. These numerical results are fully consistent with recent experimental findings that the N-terminal residues are not part of the fibril by forming α-helical structure but rather play a significant role in stabilizing the amyloidogenic region available for the fibrillation.
胰岛中负责 II 型糖尿病的胰岛素产生β细胞的丧失与胰岛淀粉样沉积有关。这些沉积物的主要成分是由 37 个残基的人胰岛淀粉样多肽（也称为胰岛淀粉样肽，简称 IAPP）形成的淀粉样原纤维。尽管这些原纤维具有交叉β结构，但在聚集的早期阶段形成的瞬态低聚物的结构仍然难以捉摸。在这项研究中，我们应用哈密顿温度复制交换分子动力学来描述全长 hIAPP 二聚体在存在和不存在 Cys2-Cys7 二硫键的情况下的结构和热力学。我们将这些结果与单体和二聚体形式的大鼠 IAPP（rIAPP）的结果进行了比较，这些大鼠 IAPP 带有一个二硫键，在 C 端区域与 hIAPP 有 6 个氨基酸的差异，但它不能形成纤维。使用粗粒化蛋白力场（OPEP-高效肽结构预测优化势能），每个系统的总运行时间为 10-28 μs，我们表明，序列在 N 端区域采样α-螺旋结构，但该二级元件的长度较短，并且没有二硫键的链稳定性较差（有桥接的 hIAPP 为 5-16 个残基，无桥接的 hIAPP 为 10-16 个残基）。这种α-螺旋是形成低聚物的一个重要瞬态阶段。在 hIAPP 的淀粉样区域的 C 端，观察到残基 17-26 和 30-35 的β-链。相反，无论是单体还是二聚体 rIAPP，在 C 端都没有观察到明显的β-折叠含量。这些数值结果与最近的实验结果完全一致，即 N 端残基不是纤维的一部分，而是通过形成α-螺旋结构来稳定纤维形成所需的淀粉样区域，从而发挥重要作用。
