Stability and structure of oligomers of the Alzheimer peptide Aβ16-22:: From the dimer to the 32-mer
Stability and structure of oligomers of the Alzheimer peptide Aβ16-22:: From the dimer to the 32-mer
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DOI：
10.1529/biophysj.106.088542
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发表时间：
2006-11-01
影响因子：
3.4
通讯作者：
Petronzio, Roberto
中科院分区：
文献类型：
--
作者：
Rohrig, Ute F.;Laio, Alessandro;Petronzio, Roberto
一些神经退行性疾病，如阿尔茨海默病、帕金森病和亨廷顿病，都与由不同多肽形成的淀粉样蛋白原纤维有关。我们利用原子细节分子动力学模拟和明确的溶剂研究了阿尔茨海默β -淀粉样肽片段A β(16-22)不同大小的低聚物的结构和稳定性。我们发现只有大的低聚物形成稳定的β -片聚集体，最小的核大小为8-16肽的顺序。这种效果归因于更好的疏水接触和在更大的组件中更好地屏蔽主-主氢键与溶剂的接触。此外，观察到的具有不同层数的β -片聚集体的稳定性可以根据它们的溶剂可及表面积来解释。根据薄片之间的堆叠界面，我们观察到直或扭曲的结构，这可能与实验观察到的淀粉样原纤维多态性有关。为了与实验数据进行比较，我们计算了它的x射线衍射图。在实验和理论确定的反射之间发现了良好的一致性，这表明我们的模型确实与体外发现的结构非常相似。
Several neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases are associated with amyloid fibrils formed by different polypeptides. We probe the structure and stability of oligomers of different sizes of the fragment A beta(16-22) of the Alzheimer beta-amyloid peptide using atomic-detail molecular dynamics simulations with explicit solvent. We find that only large oligomers form a stable beta-sheet aggregate, the minimum nucleus size being of the order of 8-16 peptides. This effect is attributed to better hydrophobic contacts and a better shielding of backbone-backbone hydrogen bonds from the solvent in bigger assemblies. Moreover, the observed stability of beta-sheet aggregates with a different number of layers can be explained on the basis of their solvent-accessible surface area. Depending on the stacking interface between the sheets, we observe straight or twisted structures, which could be linked to the experimentally observed polymorphism of amyloid fibrils. To compare our 32-mer structure to experimental data, we calculate its x-ray diffraction pattern. Good agreement is found between experimentally and theoretically determined reflections, suggesting that our model indeed closely resembles the structures found in vitro.