Istituto Dalle Molle di Studi sull'Intelligenza Artificiale (IDSIA), Scuola Universitaria Professionale della Svizzera Italiana (SUPSI), Università della Svizzera Italiana (USI), Centro Galleria 2, CH-6928 Manno, Switzerland.
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Corso Duca degli Abruzzi 24, IT-10128 Torino, Italy.
Int J Mol Sci. 2018 Feb 14;19(2):571. doi: 10.3390/ijms19020571.
Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ and Aβ. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ peptides can only assume U-shaped conformations while Aβ can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.
阿尔茨海默病是最致命的神经退行性疾病，其特征是患者大脑中淀粉样 β (Aβ) 寡聚物的聚集和沉积。人类中存在两种主要的 Aβ 变体：Aβ 和 Aβ。前者在斑块中含量最丰富，而后者是毒性最强的物种，并且更快地形成纤维。有趣的是，Aβ 肽的纤维只能呈现 U 形构象，而 Aβ 还可以排列成最近发现的 S 形三股链。由于蛋白质构象排列的改变与细胞毒性和疾病进展速度相关，因此在分子水平上描述淀粉样纤维的构象动力学非常重要。在这项工作中，进行了 Replica Exchange 分子动力学模拟，以比较 U 形和 S 形 Aβ 小纤维的构象动力学。我们的计算结果支持了最近提出的 S 形模型的稳定性，因为涉及 C 末端残基的最大化相互作用。另一方面，U 形基序的特征是显著的扭曲，导致更无序的组装。我们工作的结果表明，蛋白质聚集体的分子结构可能在纤维的形成和构象稳定性中起关键作用。
