Molecular modeling of the Aβ1-42 peptide from Alzheimer's disease
Molecular modeling of the Aβ1-42 peptide from Alzheimer's disease
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DOI：
10.1093/protein/11.9.761
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发表时间：
1998-09-01
期刊：
影响因子：
--
通讯作者：
Roher, AE
中科院分区：
文献类型：
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作者：
Chaney, MO;Webster, SD;Roher, AE
通过序列同源性、线方法和实验观察，预测了阿尔茨海默病Aβ1-42肽的三维结构。Aβ分子显示了一只希腊关键飞蛾，它有四条反平行的β链。为了屏蔽热力学上不利的结构域，两个Aβ分子相互作用，形成具有亲水表面和疏水核心的贝塔桶结构。二聚体的N-末端结构域形成缝隙，非极性的C-末端容纳在缝隙中以产生直径为27×32埃的球形结构。或者，两个相对的二聚体的C-末端结构域可以被延伸以形成反平行的β-折叠，这些构建块的堆积产生螺旋原丝。为了创造一个热力学上更有利的结构，三个原细丝结合成一个右旋三螺旋，一个疏水的β-折叠完全被由残基1-28组成的亲水的β-桶包围。两条三股螺旋可以进一步结合成右旋淀粉样丝。虽然我们的模型没有满足所有预期的标准，但它仍然显示了一系列自然处置的结构特征，这些特征是由其他生物物理研究揭示的，利用合成的Aβ肽，这些特征在Aβ拓扑结构、纤维形成和细胞毒性方面具有功能意义，该模型也表明Aβ可能不以热力学稳定的构象存在，而是作为亚稳态二聚体结构的集合，其中一些能够产生延长的C-末端反平行的β-折叠，在促进纤维形成方面是必不可少的。
The three-dimensional structure of the Alzheimer's disease A beta 1-42 peptide was predicted by sequence homology, threading approaches and by experimental observations. The A beta molecule displayed a Greek key moth with four antiparallel beta-strands. To shield thermodynamically unfavorable domains, two A beta molecules interact with each other to generate a beta-barrel structure with a hydrophilic surface and a hydrophobic core. The N-terminal domains of the dimer form crevices into which the non-polar C-termini are accommodated to yield a globular structure 27X32 Angstrom in diameter. Alternatively, the C-terminal domains of two opposing dimers could be extended to form an antiparallel beta-sheet, The stacking of these building blocks generates a helical protofilament. To create a thermodynamically more favorable structure, three protofilaments associate into a right-handed triple helix with a hydrophobic beta-sheet completely surrounded by the hydrophilic beta-barrels made of residues 1-28. Two triple helical strands can further associate into a right-handed amyloid filament. Although our model did not meet all the expected criteria, it nevertheless exhibited a series of naturally disposed structural features, revealed by other biophysical studies utilizing synthetic A beta peptides, These characteristics are of functional significance in terms of A beta-topology, fibril formation and cytotoxicity, The model also suggests that A beta may not exist in a thermodynamically stable conformation, but rather as an ensemble of metastable dimeric structures some of which are capable of generating an extended C-terminal antiparallel beta-sheet essential in the promotion of fibrillogenesis.