Chong Song-Ho, Yim Janghyun, Ham Sihyun
Department of Chemistry, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-Ku, Seoul 140-742, Korea.
Mol Biosyst. 2013 May;9(5):997-1003. doi: 10.1039/c2mb25457c.
Alzheimer's disease is a neurodegenerative disorder characterized by progressive deposition of amyloid-beta (Aβ) peptides in brain parenchyma and cerebral blood vessels. Several pathogenic familial mutations of Aβ peptides have been identified that exhibit enhanced neurotoxicity and aggregative ability. However, knowledge of the structural characteristics of those Aβ mutants is still limited. Here, we report multiple all-atom molecular dynamics simulations of the wild-type 42-residue Aβ peptide (Aβ42) and its Flemish (A21G), Arctic (E22G), Dutch (E22Q), Italian (E22K), and Iowa (D23N) familial mutants in explicit water. After validating our simulations by comparison with available experimental data, we examined common/different features in the secondary and tertiary structures of the wild-type and five familial mutants of Aβ42. We found that Aβ42 peptides display quite heterogeneous secondary and tertiary structure ensembles. Such structural heterogeneity in the monomeric state would facilitate interconversions between various secondary structures during the formation of a β-sheet-rich amyloid fibril, and may also serve as a structural basis of the amyloid polymorphism.
阿尔茨海默病是一种神经退行性疾病，其特征是淀粉样β（Aβ）肽在脑实质和脑血管中进行性沉积。已鉴定出几种具有增强神经毒性和聚集能力的Aβ肽致病性家族突变。然而，关于这些Aβ突变体结构特征的了解仍然有限。在此，我们报告了野生型42个残基的Aβ肽（Aβ42）及其佛兰芒（A21G）、北极（E22G）、荷兰（E22Q）、意大利（E22K）和爱荷华（D23N）家族突变体在显式水中的多个全原子分子动力学模拟。通过与现有实验数据比较验证我们的模拟后，我们研究了Aβ42野生型和五个家族突变体二级和三级结构中的共同/不同特征。我们发现Aβ42肽表现出相当异质的二级和三级结构集合。单体状态下的这种结构异质性将促进富含β-折叠的淀粉样纤维形成过程中各种二级结构之间的相互转换，并且还可能作为淀粉样多态性的结构基础。
