Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Jülich GmbH , 52425 Jülich, Germany.
Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf , 40225 Düsseldorf, Germany.
J Am Chem Soc. 2018 Jan 10;140(1):319-327. doi: 10.1021/jacs.7b10343. Epub 2017 Dec 28.
One of the main research topics related to Alzheimer's disease is the aggregation of the amyloid-β peptide, which was shown to follow different pathways for the two major alloforms of the peptide, Aβ40 and the more toxic Aβ42. Experimental studies emphasized that oligomers of specific sizes appear in the early aggregation process in different quantities and might be the key toxic agents for each of the two alloforms. We use transition networks derived from all-atom molecular dynamics simulations to show that the oligomers leading to the type of oligomer distributions observed in experiments originate from compact conformations. Extended oligomers, on the other hand, contribute more to the production of larger aggregates thus driving the aggregation process. We further demonstrate that differences in the aggregation pathways of the two Aβ alloforms occur as early as during the dimer stage. The higher solvent-exposure of hydrophobic residues in Aβ42 oligomers contributes to the different aggregation pathways of both alloforms and also to the increased cytotoxicity of Aβ42.
阿尔茨海默病相关的主要研究课题之一是淀粉样蛋白-β肽的聚集，研究表明，该肽的两种主要同种型 Aβ40 和毒性更强的 Aβ42 遵循不同的途径。实验研究强调，在不同数量的早期聚集过程中会出现特定大小的寡聚物，并且可能是两种同种型的关键毒性剂。我们使用从头算分子动力学模拟得出的转变网络表明，导致实验中观察到的寡聚物分布类型的寡聚物源自于紧凑的构象。另一方面，扩展的寡聚物则更多地导致更大的聚集体的产生，从而驱动聚集过程。我们进一步证明，两种 Aβ同种型的聚集途径差异早在二聚体阶段就已经出现。Aβ42 寡聚物中疏水性残基的更高溶剂暴露程度导致了两种同种型的不同聚集途径，也导致了 Aβ42 的细胞毒性增加。
