State Key Laboratory of Precision Spectroscopy, Department of Physics, Institute of Theoretical and Computational Science, East China Normal University, Shanghai, China.
J Phys Chem B. 2012 Dec 6;116(48):13991-9. doi: 10.1021/jp308708h. Epub 2012 Nov 26.
The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. Recently, protofibril models for amylin, i.e., the 37-residue human islet amyloid polypeptide or hIAPP were suggested by two groups based on NMR (Biochemistry 2007, 46, 13505-13522) and X-ray (Protein Sci. 2008, 17, 1467-1474) techniques. However, there are significant differences in the two models which maybe originate from the polymorphic nature of amylin fibrils. To obtain further insights into the packing and stability features of the different models, we performed a series of molecular dynamics simulations on them. Our analysis showed that even pairs of β-sheets composed of a limited number of β-strands are stable in the 100-ns simulations, which suggests that steric zipper interactions at a β-sheet-β-sheet interface strongly contribute to the stability of these amyloid aggregates. For both models, outer strands are more flexible, which might coincide with the dynamical requirement that outer strands act as growing sites facilitating conformational changes of new incoming chains. Moreover, simulation results showed that the X-ray models are structurally more compact than the NMR models and have more intimate patterns, which lead to more rigid amyloid models. As a result, the X-ray models are energetically more stable than the NMR models. Further modeling analyses verify the most likely amylin fibril model among both NMR and X-ray models. Upon further study of the force-induced dissociation of a single chain from the protofibrils, the binding energy and the mechanical stability of the fibril models are revealed. On these bases, it is possible to reconcile the crystallographic and the NMR data on the basic amylin fiber unit.
淀粉样纤维的结构特征是结构生物学中研究最广泛的领域之一。最近，两组基于 NMR（生物化学 2007，46，13505-13522）和 X 射线（蛋白质科学 2008，17，1467-1474）技术的研究人员提出了淀粉样蛋白原纤维模型，即 37 个残基的人胰岛淀粉样多肽或 hIAPP。然而，这两种模型之间存在显著差异，这可能源于淀粉样纤维的多态性。为了进一步深入了解不同模型的堆积和稳定性特征，我们对它们进行了一系列分子动力学模拟。我们的分析表明，即使是由有限数量的β-链组成的β-折叠对，在 100-ns 的模拟中也是稳定的，这表明β-折叠对之间的空间拉链相互作用对这些淀粉样聚集物的稳定性有很强的贡献。对于这两种模型，外链更具柔性，这可能与动态要求相吻合，即外链作为生长点，有利于新进入链的构象变化。此外，模拟结果表明，X 射线模型在结构上比 NMR 模型更紧凑，具有更密切的模式，导致更刚性的淀粉样模型。因此，X 射线模型在能量上比 NMR 模型更稳定。进一步的建模分析验证了两种 NMR 和 X 射线模型中最有可能的淀粉样纤维模型。在进一步研究单链从原纤维中力诱导解离的过程中，揭示了纤维模型的结合能和机械稳定性。在此基础上，有可能调和基本淀粉样纤维单元的晶体学和 NMR 数据。
