Šarić Anđela, Chebaro Yassmine C, Knowles Tuomas P J, Frenkel Daan
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom
Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17869-74. doi: 10.1073/pnas.1410159111. Epub 2014 Dec 1.
Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet-rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory.
蛋白质寡聚体被认为是多种淀粉样蛋白相关疾病中的毒性因子。然而，寡聚体是淀粉样纤维形成过程中的必要步骤还是仅仅是一种危险的副产物，这一问题仍未得到解决。类似地，淀粉样蛋白成核过程是经典的一步成核过程还是涉及预成核聚集体的两步过程也尚未明确。我们使用粗粒度计算机模拟来研究肽之间非特异性吸引力对淀粉样纤维形成基础的初级成核过程的影响。我们发现，对于没有吸引力的肽，经典的一步成核机制是可能的，但仅在非生理高肽浓度下。在模拟生理相关状态的低肽浓度下，肽间的吸引相互作用对于纤维形成至关重要。成核不可避免地通过涉及原纤维前体寡聚体的两步机制发生。我们表明，寡聚体不仅有助于肽相互接触，还创造了一个促进单体转化为富含β折叠的纤维特征形式的环境。成核通常不通过最普遍的寡聚体进行，而是通过仅在罕见波动中观察到的寡聚体大小进行，这就是为什么这种聚集体可能难以通过实验捕获。最后，我们发现淀粉样纤维的成核不能用经典成核理论来描述：在两步机制中，临界核尺寸随着浓度和肽间相互作用的增加而增加，这与经典成核理论的预测直接相反。
