Department of Chemistry, The University of Texas at Austin, Austin, TX 78712.
Department of Chemistry, Boston University, Boston, MA 02215.
Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):19926-19937. doi: 10.1073/pnas.2002570117. Epub 2020 Jul 30.
The early events in the aggregation of the intrinsically disordered peptide, amyloid-β (Aβ), involve transitions from the disordered free energy ground state to assembly-competent states. Are the fingerprints of order found in the amyloid fibrils encoded in the conformations that the monomers access at equilibrium? If so, could the enhanced aggregation rate of Aβ42 compared to Aβ40 be rationalized from the sparsely populated high free energy states of the monomers? Here, we answer these questions in the affirmative using coarse-grained simulations of the self-organized polymer-intrinsically disordered protein (SOP-IDP) model of Aβ40 and Aβ42. Although both the peptides have practically identical ensemble-averaged properties, characteristic of random coils (RCs), the conformational ensembles of the two monomers exhibit sequence-specific heterogeneity. Hierarchical clustering of conformations reveals that both the peptides populate high free energy aggregation-prone ([Formula: see text]) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the [Formula: see text] states of Aβ42 peptide is smaller than that for Aβ40. By relating the populations of excited states of the two peptides to the fibril formation time scales using an empirical formula, we explain nearly quantitatively the faster aggregation rate of Aβ42 relative to Aβ40. The [Formula: see text] concept accounts for fibril polymorphs, leading to the prediction that the less stable [Formula: see text] state of Aβ42, encoding for the U-bend fibril, should form earlier than the structure with the S-bend topology, which is in accord with Ostwald's rule rationalizing crystal polymorph formation.
无序肽淀粉样-β(Aβ)聚集的早期事件涉及从无序自由能基态到组装竞争态的转变。在纤维中发现的有序指纹是否编码在单体在平衡时访问的构象中?如果是这样,与 Aβ40 相比,Aβ42 增强的聚集速率是否可以从单体稀疏的高自由能状态合理化?在这里,我们使用 Aβ40 和 Aβ42 的自组织聚合物-无序蛋白(SOP-IDP)模型的粗粒度模拟来肯定地回答这些问题。尽管两种肽都具有几乎相同的随机卷曲(RC)的平均集合特性,但两种单体的构象集合都表现出序列特异性的异质性。构象的层次聚类表明,两种肽都具有高自由能聚集倾向的状态([Formula: see text]),类似于纤维结构中的单体。Aβ42 肽的基态(RC)和[Formula: see text]状态之间的自由能间隙小于 Aβ40。通过使用经验公式将两种肽的激发态的种群与纤维形成时间尺度相关联,我们几乎可以定量地解释 Aβ42 相对于 Aβ40 的更快聚集速率。[Formula: see text]概念解释了纤维的多晶型,从而预测 Aβ42 的不太稳定的[Formula: see text]状态,编码为 U 形纤维,应该比具有 S 形拓扑结构的纤维更早形成,这与奥斯特瓦尔德规则合理化晶体多晶型形成一致。