Zhang Mingzhen, Hu Rundong, Chen Hong, Chang Yung, Gong Xiong, Liu Fufeng, Zheng Jie
Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio 44325, USA.
Phys Chem Chem Phys. 2015 Apr 28;17(16):10373-82. doi: 10.1039/c4cp05658b.
Cross-sequence interactions between different amyloid peptides are important not only for the fundamental understanding of amyloid aggregation and polymorphism mechanisms, but also for probing a potential molecular link between different amyloid diseases. Here, we computationally modeled and simulated a series of hybrid hIAPP (human islet amyloid polypeptide)-rIAPP (rat islet amyloid polypeptide) assemblies and probed their structural stability, lateral association, and interfacial interactions using combined peptide-packing search, molecular dynamics (MD) simulations, and the Monte Carlo sampling method. We then identified a number of stable and highly populated hIAPP-rIAPP assemblies at the lowest energy states, in which hIAPP and rIAPP oligomers were stacked laterally on top of each other to form supramolecular β-sheet double layers in an antiparallel fashion. These hIAPP-rIAPP assemblies adopted different interfaces formed by C-terminal β-sheets of hIAPP and rIAPP oligomers (hCCr), N-terminal β-sheets of hIAPP and rIAPP oligomers (hNNr), and alternative N-terminal/C-terminal β-sheets of hIAPP and rIAPP oligomers (hNCr and hCNr). Different interfaces along with distinct interfacial residue packings provided different driving interfacial forces to laterally associate two β-sheet layers of hIAPP and rIAPP together for forming polymorphic hIAPP-rIAPP assemblies. Such lateral association between hIAPP and rIAPP not only explained the experimentally observed cross-seeding behavior of hIAPP and rIAPP, but also demonstrated the co-existence of polymorphic amyloid cross-seeding species. A cross-seeding mechanism for hIAPP and rIAPP aggregation was proposed on the basis of our simulated models and experimental data. This work provides a better understanding of cross-seeding aggregation and polymorphism mechanisms of amyloidogenesis.
不同淀粉样肽之间的跨序列相互作用不仅对于从根本上理解淀粉样聚集和多态性机制很重要，而且对于探究不同淀粉样疾病之间潜在的分子联系也很重要。在此，我们通过计算对一系列混合的人胰岛淀粉样多肽（hIAPP）-大鼠胰岛淀粉样多肽（rIAPP）组装体进行建模和模拟，并使用联合肽堆积搜索、分子动力学（MD）模拟和蒙特卡罗采样方法探究它们的结构稳定性、横向缔合和界面相互作用。然后，我们在最低能量状态下确定了许多稳定且大量存在的hIAPP-rIAPP组装体，其中hIAPP和rIAPP寡聚体以反平行方式彼此横向堆叠形成超分子β-折叠双层。这些hIAPP-rIAPP组装体采用了由hIAPP和rIAPP寡聚体的C端β-折叠（hCCr）、hIAPP和rIAPP寡聚体的N端β-折叠（hNNr）以及hIAPP和rIAPP寡聚体的交替N端/C端β-折叠（hNCr和hCNr）形成的不同界面。不同的界面以及独特的界面残基堆积为将hIAPP和rIAPP的两个β-折叠层横向缔合在一起以形成多态性hIAPP-rIAPP组装体提供了不同的驱动界面力。hIAPP和rIAPP之间的这种横向缔合不仅解释了实验观察到的hIAPP和rIAPP的交叉播种行为，还证明了多态性淀粉样交叉播种物种的共存。基于我们的模拟模型和实验数据，提出了hIAPP和rIAPP聚集的交叉播种机制。这项工作有助于更好地理解淀粉样蛋白生成的交叉播种聚集和多态性机制。
