Molecular Mechanism of Misfolding and Aggregation of Aβ(13-23)
Molecular Mechanism of Misfolding and Aggregation of Aβ(13-23)
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DOI：
10.1021/jp402938p
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发表时间：
2013-05-23
影响因子：
3.3
通讯作者：
Lyubchenko, Yuri L.
中科院分区：
文献类型：
--
作者：
Lovas, Sandor;Zhang, Yuliang;Lyubchenko, Yuri L.
淀粉样β蛋白(Aβ)多肽的错误折叠和自组装成聚集体是阿尔茨海默病发生发展的分子标志，但多肽聚集的分子机制尚不清楚。在这里，我们结合原子力显微镜(AFM)和分子动力学(MD)模拟来表征Aβ多肽的错误折叠过程。动态力谱分析表明，该多肽形成稳定的二聚体，其寿命与1 S相似。在分子动力学模拟过程中，单体逐渐采用与初始结构无关的基本相似的非结构构象。然而，当两个单体接近时，它们的结构发生了巨大的变化，两个单体的构象空间变得有限。单体的反平行排列导致了β-折叠构象的协同形成。包括氢键、盐桥和侧链的弱极性相互作用在内的相互作用稳定了二聚体的结构。在外力作用下，二聚体，就像在原子力显微镜实验中一样，以合作的方式解离。因此，Aβ肽的错误折叠是通过失去构象灵活性和形成稳定的二聚体来进行的，这表明它们在随后的Aβ聚集过程中起着关键作用。
The misfolding and self-assembly of the amyloid-beta (A beta) peptide into aggregates is a molecular signature of the development of Alzheimer's disease, but molecular mechanisms of the peptide aggregation remain unknown. Here, we combined Atomic Force Microscopy (AFM) and Molecular Dynamics (MD) simulations to characterize the misfolding process of an A beta peptide. Dynamic force spectroscopy AFM analysis showed that the peptide forms stable dimers with a lifetime of similar to 1 s. During MD simulations, isolated monomers gradually adopt essentially similar nonstructured conformations independent from the initial structure. However, when two monomers approach their structure changes dramatically, and the conformational space for the two monomers become restricted. The arrangement of monomers in antiparallel orientation leads to the cooperative formation of beta-sheet conformation. Interactions, including hydrogen bonds, salt bridges, and weakly polar interactions of side chains stabilize the structure of the dimer. Under the applied force, the dimer, as during the AFM experiments, dissociates in a cooperative manner. Thus, misfolding of the A beta peptide proceeds via the loss of conformational flexibility and formation of stable dimers suggesting their key role in the subsequent A beta aggregation process.