Huet Alexis, Derreumaux Philippe
Laboratoire de Biochimie Théorique, UPR 9080, Centre National de la Recherche Scientifique, Institut de Biologie Physico-Chimique, et Université Paris, Paris, France.
Biophys J. 2006 Nov 15;91(10):3829-40. doi: 10.1529/biophysj.106.090993. Epub 2006 Aug 4.
Soluble oligomers of the amyloid beta-protein (Abeta) are linked to Alzheimer's disease. Irrespective of the nature of the nucleus before fibril growth, dimers are essential species in Abeta assembly, but their transient character has precluded, thus far, high-resolution structure determination. We have investigated the effects of the point mutation A21G on Abeta dimers by performing high temperature all-atom molecular dynamics simulations of Abeta(40), Abeta(42), and their Flemish variants (A21G) starting from their fibrillar conformations. Abeta dimers are found in equilibrium between various topologies, and the absence of common structural features shared by the four species makes problematic the design of a unique inhibitor for blocking dimers. We also show that the impact of the point mutation A21G on Abeta structure and dynamics varies from Abeta(40) to Abeta(42). Finally, we provide a possible structural explanation for the reduced aggregation rate of Abeta fibrils containing the Flemish disease-causing mutation.
淀粉样β蛋白（Aβ）的可溶性寡聚体与阿尔茨海默病有关。无论原纤维生长之前核的性质如何，二聚体都是Aβ组装过程中的关键物种，但到目前为止，它们的瞬态特性使得高分辨率结构测定难以实现。我们通过对Aβ(40)、Aβ(42)及其佛兰芒变体（A21G）从其纤维状构象开始进行高温全原子分子动力学模拟，研究了点突变A21G对Aβ二聚体的影响。发现Aβ二聚体在各种拓扑结构之间处于平衡状态，并且这四种物种缺乏共同的结构特征，这使得设计一种独特的抑制剂来阻断二聚体变得困难。我们还表明，点突变A21G对Aβ结构和动力学的影响因Aβ(40)和Aβ(42)而异。最后，我们为含有佛兰芒致病突变的Aβ原纤维聚集速率降低提供了一种可能的结构解释。
