Structure and Thermodynamics of Amylin Dimer Studied by Hamiltonian-Temperature Replica Exchange Molecular Dynamics Simulations
Structure and Thermodynamics of Amylin Dimer Studied by Hamiltonian-Temperature Replica Exchange Molecular Dynamics Simulations
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哈密顿-温度复制交换分子动力学模拟研究胰淀素二聚体的结构和热力学
DOI：
10.1021/jp108870q
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发表时间：
2011-03-31
影响因子：
3.3
通讯作者：
Wei, Guanghong
中科院分区：
文献类型：
--
作者：
Laghaei, Rozita;Mousseau, Normand;Wei, Guanghong
胰岛朗格汉斯岛中负责产生胰岛素的β细胞的缺失与胰岛淀粉样沉积物有关，这与II型糖尿病相关。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（hIAPP，也称为胰淀素）形成的淀粉样纤维。尽管这些纤维通过交叉β结构得到了很好的表征，但在聚集早期形成的瞬时寡聚体的结构仍然难以捉摸。在这项研究中，我们应用哈密顿温度副本交换分子动力学来表征在存在和不存在Cys2 - Cys7二硫键的情况下全长hIAPP二聚体的结构和热力学。我们将这些结果与具有二硫键的大鼠IAPP（rIAPP）的单体和二聚体形式所获得的结果进行比较，大鼠IAPP在C末端区域与hIAPP有6个氨基酸的差异，并且它不能形成纤维。使用粗粒度蛋白质力场（OPEP——用于高效肽结构预测的优化势），对每个所研究的系统运行总计10 - 28微秒，我们表明序列在N末端区域呈现α - 螺旋结构，但对于没有二硫键的链，这种二级结构元件的长度更短且稳定性更差（有二硫键的hIAPP为残基5 - 16，没有二硫键的hIAPP为10 - 16）。已知这种α - 螺旋是寡聚体形成过程中的一个重要瞬时阶段。在C末端，即hIAPP的淀粉样形成区域，可以看到残基17 - 26和30 - 35处的β - 链。相反，对于单体或二聚体rIAPP，在C末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发现完全一致，即N末端残基通过形成α - 螺旋结构不是纤维的一部分，而是在稳定可用于纤维形成的淀粉样形成区域中起着重要作用。
The loss of the insulin-producing beta-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 beta 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 mu s per system studied, we show that sequences sample alpha-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 a-helix is known to be an important transient stage in the formation of oligomers. In the C-terminal, the amyloidogenic region of hIAPP, beta-strands are seen for residues 17-26 and 30-35. On the contrary, no significant beta-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 a-helical structure but rather play a significant role in stabilizing the amyloidogenic region available for the fibrillation.