研究肽长度和致病突变如何改变淀粉样β单体的结构集合。
Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer.
机构信息
Department of Chemistry, Stanford University, Stanford, California, USA.
出版信息
Biophys J. 2012 Jan 18;102(2):315-24. doi: 10.1016/j.bpj.2011.12.002.
The aggregation of amyloid beta (Aβ) peptides plays an important role in the development of Alzheimer's disease. Despite extensive effort, it has been difficult to characterize the secondary and tertiary structure of the Aβ monomer, the starting point for aggregation, due to its hydrophobicity and high aggregation propensity. Here, we employ extensive molecular dynamics simulations with atomistic protein and water models to determine structural ensembles for Aβ(42), Aβ(40), and Aβ(42)-E22K (the Italian mutant) monomers in solution. Sampling of a total of >700 microseconds in all-atom detail with explicit solvent enables us to observe the effects of peptide length and a pathogenic mutation on the disordered Aβ monomer structural ensemble. Aβ(42) and Aβ(40) have crudely similar characteristics but reducing the peptide length from 42 to 40 residues reduces β-hairpin formation near the C-terminus. The pathogenic Italian E22K mutation induces helix formation in the region of residues 20-24. This structural alteration may increase helix-helix interactions between monomers, resulting in altered mechanism and kinetics of Aβ oligomerization.
淀粉样蛋白β（Aβ）肽的聚集在阿尔茨海默病的发展中起着重要作用。尽管已经付出了大量努力，但由于 Aβ 单体的疏水性和高聚集倾向，仍然难以描述其聚集的起始点 Aβ 单体的二级和三级结构。在这里，我们采用了广泛的分子动力学模拟，使用原子蛋白质和水模型来确定溶液中 Aβ（42）、Aβ（40）和 Aβ（42）-E22K（意大利突变体）单体的结构集合。在所有原子细节中进行总计超过 700 微秒的采样，并使用显式溶剂，使我们能够观察到肽长度和致病性突变对无规 Aβ 单体结构集合的影响。Aβ（42）和 Aβ（40）具有大致相似的特征，但将肽长度从 42 减少到 40 个残基会减少 C 末端附近的β-发夹形成。致病性的意大利 E22K 突变会诱导残基 20-24 区域的螺旋形成。这种结构改变可能会增加单体之间的螺旋-螺旋相互作用，从而改变 Aβ 寡聚化的机制和动力学。
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