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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular dynamics analyses of cross-β-spine steric zipper models: β-Sheet twisting and aggregation
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Molecular dynamics analyses of cross-β-spine steric zipper models: β-Sheet twisting and aggregation

机译：跨β-脊柱立体拉链模型的分子动力学分析：β-Sheet扭曲和聚集

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摘要

The structural characterization of amyloid fibers is one of the most investigated areas in structural biology. The structural motif, denoted as steric zipper, recently discovered for the peptide GNNQQNY [Nelson, R., Sawaya, M. R., Balbirnie, M., Madsen, A. O., Riekel, C., Grothe, R. & Eisenberg, D. (2005) Nature 435, 773-778], is expected to exert strong influence in this field. To obtain further insights into the features of this unique structural motif, we report several molecular dynamics simulations of various GNNQQNY aggregates. Our analyses show that even pairs of β-sheets composed of a limited number of β-strands are stable in the 20-ns time interval considered, which suggests that steric zipper interactions at a β-sheet-β-sheet interface strongly contribute to the stability of these aggregates. Moreover, although the basic features of side chain-side chain interactions are preserved in the simulation, the backbone structure undergoes significant variations. Upon equilibration, a significant twist of the β-strands that compose the β-sheets is observed. These results demonstrate that the occurrence of steric zipper interactions is compatible with flat and twisted β-sheets. Molecular dynamics simulations carried out on two pairs of β-sheets, separated in the crystal state by a hydrated interface, lead to interesting results. The two pairs of sheets, while twisting, associate through stable peptide-peptide interactions. These findings provide insight into the mechanism that leads to the formation of higher aggregates. On these bases, it is possible to reconcile the crystallographic and the EM data on the size of the basic GNNQQNY fiber unit.
机译：淀粉样蛋白纤维的结构表征是结构生物学中研究最多的领域之一。最近发现的肽GNNQQNY [Nelson，R.，Sawaya，MR，Balbirnie，M.，Madsen，AO，Riekel，C.，Grothe，R.＆Eisenberg，D.（2005） ，《自然》（Nature）435，773-778]有望在这一领域发挥强大的影响。为了获得对该独特结构基序特征的进一步了解，我们报告了多种GNNQQNY聚集体的分子动力学模拟。我们的分析表明，即使是由有限数量的β链组成的成对的β-折叠在考虑的20 ns时间间隔内也是稳定的，这表明在β-折叠-β-折叠界面上的空间拉链相互作用极大地促进了这些骨料的稳定性。此外，尽管在模拟中保留了侧链-侧链相互作用的基本特征，但主链结构却发生了显着变化。平衡后，观察到构成β-折叠的β-链的明显扭曲。这些结果表明，立体拉链相互作用的发生与平坦的和扭曲的β-片相容。对两对β-折叠进行分子动力学模拟，结果以水合界面在晶体状态下分开，从而产生有趣的结果。这两对薄片在扭曲的同时通过稳定的肽-肽相互作用而缔合。这些发现提供了导致更高聚集体形成的机理的见解。在这些基础上，可以根据基本GNNQQNY光纤单元的大小来调整晶体学数据和EM数据。

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