Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their aggregation propensities
Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their aggregation propensities
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DOI：
10.1073/pnas.2002570117
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发表时间：
2020-08-18
影响因子：
11.1
通讯作者：
Thirumalai, D.
中科院分区：
文献类型：
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作者：
Chakraborty, Debayan;Straub, John E.;Thirumalai, D.
淀粉样蛋白-β（A β）是一种内在无序的肽，其聚集的早期过程涉及从无序自由能基态到组装能态的转变。淀粉样蛋白原纤维中的有序指纹是否编码于单体在平衡状态下的构象中？如果是这样的话，A β 42与A β 40相比增强的聚集速率是否可以从单体的稀疏分布的高自由能状态来合理化？在这里，我们肯定地回答这些问题，使用自组织聚合物-内在无序蛋白（SOP-IDP）模型的A β 40和A β 42的粗粒度模拟。虽然这两种肽具有几乎相同的集合平均特性，无规卷曲（RC）的特征，但两种单体的构象集合表现出序列特异性异质性。构象的层次聚类表明，这两种肽填充高自由能聚集倾向（N*）的状态，这类似于在原纤维结构中的单体。A β 42肽的基态（RC）和N* 态之间的自由能隙小于A β 40的自由能隙。通过使用经验公式将两种肽的激发态种群与原纤维形成时间尺度联系起来，我们几乎定量地解释了A β 42相对于A β 40更快的聚集速率。N* 概念解释了原纤维多晶型物，导致预测编码U-弯曲原纤维的A β 42的较不稳定的N* 状态应该比具有S-弯曲拓扑结构的结构更早形成，这与使晶体多晶型物形成合理化的奥斯特瓦尔德规则雅阁。
The early events in the aggregation of the intrinsically disordered peptide, amyloid-beta (A beta), 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 A beta 42 compared to A beta 40 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 A beta 40 and A beta 42. 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 (N*) states, which resemble the monomers in the fibril structure. The free energy gap between the ground (RC) and the N* states of A beta 42 peptide is smaller than that for A beta 40. 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 A beta 42 relative to A beta 40. The N* concept accounts for fibril polymorphs, leading to the prediction that the less stable N* state of A beta 42, 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.