Department of Chemical and Biomolecular Engineering, The University of Akron, Akron, Ohio, United States of America.
PLoS One. 2011;6(6):e20575. doi: 10.1371/journal.pone.0020575. Epub 2011 Jun 7.
Misfolding and self-assembly of Amyloid-β (Aβ) peptides into amyloid fibrils is pathologically linked to the development of Alzheimer's disease. Polymorphic Aβ structures derived from monomers to intermediate oligomers, protofilaments, and mature fibrils have been often observed in solution. Some aggregates are on-pathway species to amyloid fibrils, while the others are off-pathway species that do not evolve into amyloid fibrils. Both on-pathway and off-pathway species could be biologically relevant species. But, the lack of atomic-level structural information for these Aβ species leads to the difficulty in the understanding of their biological roles in amyloid toxicity and amyloid formation.
Here, we model a series of molecular structures of Aβ globulomers assembled by monomer and dimer building blocks using our peptide-packing program and explicit-solvent molecular dynamics (MD) simulations. Structural and energetic analysis shows that although Aβ globulomers could adopt different energetically favorable but structurally heterogeneous conformations in a rugged energy landscape, they are still preferentially organized by dynamic dimeric subunits with a hydrophobic core formed by the C-terminal residues independence of initial peptide packing and organization. Such structural organizations offer high structural stability by maximizing peptide-peptide association and optimizing peptide-water solvation. Moreover, curved surface, compact size, and less populated β-structure in Aβ globulomers make them difficult to convert into other high-order Aβ aggregates and fibrils with dominant β-structure, suggesting that they are likely to be off-pathway species to amyloid fibrils. These Aβ globulomers are compatible with experimental data in overall size, subunit organization, and molecular weight from AFM images and H/D amide exchange NMR.
Our computationally modeled Aβ globulomers provide useful insights into structure, dynamics, and polymorphic nature of Aβ globulomers which are completely different from Aβ fibrils, suggesting that these globulomers are likely off-pathway species and explaining the independence of the aggregation kinetics between Aβ globulomers and fibrils.
淀粉样蛋白-β（Aβ）肽错误折叠和自组装成淀粉样纤维与阿尔茨海默病的发展在病理学上有关联。在溶液中经常观察到从单体到中间寡聚物、原纤维和成熟纤维的多态 Aβ结构。一些聚集体是淀粉样纤维的途径物种，而另一些则是非途径物种，不会演变成淀粉样纤维。无论是途径物种还是非途径物种，都可能是具有生物学相关性的物种。但是，由于缺乏这些 Aβ物种的原子级结构信息，导致难以理解它们在淀粉样毒性和淀粉样形成中的生物学作用。
在这里，我们使用我们的肽包装程序和显式溶剂分子动力学（MD）模拟，对由单体和二聚体构建块组装的一系列 Aβ 球形体分子结构进行建模。结构和能量分析表明，尽管 Aβ 球形体在崎岖的能量景观中可以采用不同的能量有利但结构异构的构象，但它们仍然优先由动态二聚体亚基组织，其疏水核心由 C 末端残基形成，与初始肽包装和组织无关。这种结构组织通过最大化肽-肽相互作用和优化肽-水溶剂化来提供高结构稳定性。此外，Aβ 球形体的曲面、紧凑的尺寸和较少的β-结构使其难以转化为具有主导β-结构的其他高阶 Aβ 聚集体和纤维，表明它们可能是非淀粉样纤维的途径物种。这些 Aβ 球形体与 AFM 图像和 H/D 酰胺交换 NMR 中的总体尺寸、亚基组织和分子量的实验数据相吻合。
我们计算建模的 Aβ 球形体为 Aβ 球形体的结构、动力学和多态性质提供了有用的见解，这些性质与 Aβ 纤维完全不同，表明这些球形体可能是非途径物种，并解释了 Aβ 球形体和纤维之间聚集动力学的独立性。
