Schrödinger, Inc. , 120 West 45th Street , New York , New York 10036 , United States.
Baker Laboratory of Chemistry and Chemical Biology , Cornell University , Ithaca , New York 14853 , United States.
J Phys Chem B. 2018 Jul 19;122(28):7049-7056. doi: 10.1021/acs.jpcb.8b04647. Epub 2018 Jul 10.
One of the hallmarks of Alzheimer's disease is the formation of aggregates of the tau protein, a process that can be facilitated by the presence of fibrils formed by the amyloid β peptide (Aβ). However, the mechanism that triggers tau aggregation is still a matter of debate. The effect of Aβ fibrils on the aggregation of the repeat domain of tau (TauRD) is investigated here by employing coarse-grained molecular dynamics simulations. The results indicate that the repeat domain of tau has a high affinity for Aβ fibrils, with the GSTENLK fragment of tau driving TauRD toward the KLVFFA fragment in Aβ. Monomeric Aβ, in which the KLVFFA fragment is rarely found in an extended conformation (as in the fibril), has a low affinity for the TauRD, indicating that the ability of Aβ fibrils to bind to the TauRD depends on the KLVFFA fragment of Aβ adopting an extended conformation.
阿尔茨海默病的特征之一是 Tau 蛋白的聚集物的形成，该过程可以通过淀粉样 β 肽（Aβ）形成的纤维促进。然而，触发 Tau 聚集的机制仍然存在争议。这里通过使用粗粒度分子动力学模拟研究了 Aβ 纤维对 Tau 重复结构域（TauRD）聚集的影响。结果表明，Tau 的重复结构域对 Aβ 纤维具有高亲和力，Tau 的 GSTENLK 片段将 TauRD 驱动到 Aβ 的 KLVFFA 片段。单体 Aβ 中，KLVFFA 片段很少以伸展构象（如在纤维中）存在，对 TauRD 的亲和力低，表明 Aβ 纤维结合 TauRD 的能力取决于 Aβ 的 KLVFFA 片段采用伸展构象。
