Department of Theory and Bio-Systems, Max-Planck-Institute of Colloids and Interfaces, 14424 Potsdam, Germany.
J Phys Chem B. 2010 Nov 25;114(46):15288-95. doi: 10.1021/jp1065264. Epub 2010 Oct 22.
Alzheimer's disease is associated with the precipitation of the amyloid β (Aβ) (1-40) peptide in the form of fibrils. Among the full length peptide, smaller fragments such as Aβ (25-35) which retains the toxicity of the full length peptide are also present. Aβ's toxicity is attributed to soluble oligomers which, however, are difficult to study experimentally due to their transient nature. Here we present replica exchange molecular dynamics simulations of Aβ (25-35) dimers in explicit water. Similar to a previous study, dimers are found to exist as disordered compact in equilibrium with ordered extended fibril-like conformations. In addition, our results suggest effects from slight differences in ionic conditions and yield insights on this system in unprecedented detail. In the compact state, the peptides adopt β-hairpin or unstructured U-shaped conformations with different relative orientations. In the extended state, the peptides are outstretched and form antiparallel in- or out-of-register intermolecular β-sheets. In addition to the previous study, we reveal the driving forces governing the equilibrium between the disordered and the fibril-like state. In particular, it is shown that the compact state is favored by a high entropy while the fibril-like state is lower in energy arising from favorable covalent and electrostatic interactions between and within the peptides. Our results suggest that the transition from the compact to the fibril-like state involves reptation, i.e., a change in register of an intermolecular β-sheet without dissociation of the peptides.
阿尔茨海默病与淀粉样 β（Aβ）（1-40）肽以纤维的形式沉淀有关。在全长肽中，也存在保留全长肽毒性的较小片段，如 Aβ（25-35）。Aβ 的毒性归因于可溶性寡聚物，但由于其瞬态性质，难以在实验中进行研究。在这里，我们在明水环境中对 Aβ（25-35）二聚体进行了复制交换分子动力学模拟。与之前的研究类似，二聚体被发现以无序紧凑的形式存在，与有序延伸的纤维状构象平衡。此外，我们的结果表明离子条件的微小差异会产生影响，并以前所未有的细节深入了解该系统。在紧凑状态下，肽采用β发夹或无结构 U 形构象，具有不同的相对取向。在延伸状态下，肽伸展并形成反平行的内或外对准的分子间β-折叠。除了之前的研究，我们还揭示了控制无序和纤维状状态之间平衡的驱动力。特别是，结果表明，紧凑状态有利于高熵，而纤维状状态能量较低，这是由于肽之间和内部的共价和静电相互作用有利。我们的结果表明，从紧凑状态到纤维状状态的转变涉及蠕动，即分子间β-折叠的构象变化而不涉及肽的解离。
