Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald's rule of stages.
Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald's rule of stages.
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DOI：
10.1126/sciadv.add6921
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发表时间：
2023-03-22
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
淀粉样蛋白生成序列中从无序到组装单体状态（N*）的转变是聚集级联中的关键事件。使用一个良好校准的内在无序蛋白质（IDP）模型，我们表明，N* 状态，这与实验中发现的多态性纤维结构有相当大的相似之处，不仅出现在Aβ40和Aβ42的自由能景观的激发，但也启动聚集级联。对于Aβ42，到不同N* 态的跃迁雅阁Ostwald的阶段规则，最不稳定的结构形成在优先选择的结构之前。Aβ40和Aβ42单体景观表现出不同程度的局部挫折，我们表明这在决定随后的自组装方面具有深远的意义。使用动力学转换网络，我们说明，最有利的二聚路线进行通过N* 状态。我们认为，奥斯特瓦尔德规则也适用于肉瘤和多聚谷氨酰胺蛋白融合的聚集。淀粉样蛋白β单体采用短暂的纤维状顺序，遵循奥斯特瓦尔德阶段规则。
The transition from a disordered to an assembly-competent monomeric state (N*) in amyloidogenic sequences is a crucial event in the aggregation cascade. Using a well-calibrated model for intrinsically disordered proteins (IDPs), we show that the N* states, which bear considerable resemblance to the polymorphic fibril structures found in experiments, not only appear as excitations in the free energy landscapes of Aβ40 and Aβ42, but also initiate the aggregation cascade. For Aβ42, the transitions to the different N* states are in accord with Ostwald’s rule of stages, with the least stable structures forming ahead of thermodynamically favored ones. The Aβ40 and Aβ42 monomer landscapes exhibit different extents of local frustration, which we show have profound implications in dictating subsequent self-assembly. Using kinetic transition networks, we illustrate that the most favored dimerization routes proceed via N* states. We argue that Ostwald’s rule also holds for the aggregation of fused in sarcoma and polyglutamine proteins. Amyloid beta monomers adopt transient fibrillar order following Ostwald's rule of stages.
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影响因子：
56.9
作者：
GOLDE, TE;ESTUS, S;YOUNKIN, SG
通讯作者：
YOUNKIN, SG
DOI：
10.1137/0109047
发表时间：
1961-01-01
期刊：
JOURNAL OF THE SOCIETY FOR INDUSTRIAL AND APPLIED MATHEMATICS
影响因子：
--
作者：
GOMORY, RE;HU, TC
通讯作者：
HU, TC
DOI：
10.1073/pnas.2002570117
发表时间：
2020-08-18
影响因子：
11.1
作者：
Chakraborty, Debayan;Straub, John E.;Thirumalai, D.
通讯作者：
Thirumalai, D.
影响因子：
3.4
作者：
Chandra, Bappaditya;Bhowmik, Debanjan;Madhu, Perunthiruthy K.
通讯作者：
Madhu, Perunthiruthy K.
影响因子：
25
作者：
Cleary, JP;Walsh, DM;Ashe, KH
通讯作者：
Ashe, KH