Amyloid beta(1-42) in aqueous environments: Effects of ionic strength and E22Q (Dutch) mutation
Amyloid beta(1-42) in aqueous environments: Effects of ionic strength and E22Q (Dutch) mutation
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DOI：
10.1016/j.bbapap.2013.08.010
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发表时间：
2013-12-01
影响因子：
3.2
通讯作者：
Palese, Luigi L.
中科院分区：
文献类型：
--
作者：
Bossis, Fabrizio;Palese, Luigi L.
阿尔茨海默病特征的细胞外斑块的发展与淀粉样肽的聚集有关。A -42肽是最容易聚集的物种，一些错义突变形式增加了这种聚集能力。由于A β -42在水溶液中的溶解度较差，分子动力学研究了A β -42在水中的构象转变。在这里，我们报告了水环境中A β -42肽的全原子分子动力学分析，使用在各向同性、低极性介质中获得的结构作为起始构象，代表了膜结合物种的合理模型。虽然以前的研究通常表明A -42在水溶液中大部分是非结构化的，但在这里，我们报道了这种肽可以采用部分折叠的结构。离子强度的重要性也被研究，表明在生理离子强度条件下，一个环稳定静电相互作用涉及Lys28建立。此外，除了稳定的α -螺旋结构外，我们还观察到3（10）螺旋的外观，类似于实验报道的A -40物种。探讨了E22Q （Dutch）突变在高离子强度条件下的影响。我们发现这种突变对a β -42的结构有巨大的影响。与野生型的部分折叠但扩展的构象不同，E22Q由于疏水残基的聚集而呈现双螺旋折叠构象。(C) 2013 Elsevier B.V.版权所有
Development of extracellular plaques characteristic of Alzheimer's disease is related to aggregation of amyloid peptides. The A beta-42 peptide is the most aggregation prone species, and some missense mutant forms increase this aggregation ability. Due to its poor solubility as monomer in aqueous solutions, A beta-42 conformational transitions in water have been largely investigated by molecular dynamics. Here we report an all-atom molecular dynamics analysis of the A beta-42 peptide in aqueous environment using as starting conformation a structure obtained in an isotropic, low-polarity medium, representing a plausible model for the membrane-bound species. While previous studies commonly show that A beta-42 is largely unstructured in aqueous solution, here we report that this peptide can adopt partially folded structures. Importance of ionic strength has been also investigated, showing that at physiological ionic strength condition a loop stabilizing electrostatic interaction involving Lys28 builds up. In addition, besides stable alpha-helix structures, we observe the appearance of 3(10) helix, similar to what was reported experimentally for the A beta-40 species. The effect of E22Q (Dutch) mutation in high ionic strength condition has been explored. We show that this mutation has a dramatic impact on the A beta-42 structure. Instead of a partially folded, but extended, conformation obtained with the wild type, the E22Q assumes a two-helix collapsed one due to the clustering of hydrophobic residues. (C) 2013 Elsevier B.V. All rights reserved.