Takeda Takako, Klimov Dmitri K
Department of Bioinformatics and Computational Biology, George Mason University, Manassas, Virginia 20110, USA.
Biophys J. 2008 Aug;95(4):1758-72. doi: 10.1529/biophysj.108.131698. Epub 2008 May 23.
Using all-atom molecular dynamics, we study the temperature-induced dissociation of Abeta monomers from the fibril protofilament. To accelerate conformational sampling, simulations are performed at elevated temperatures and peptide concentrations. By computing free energy disconnectivity graphs we mapped the free energy landscape of monomers on the surface of Abeta fibril. We found that Abeta monomers sample diverse sets of low free energy states with different degrees of association with the fibril. Some of these states have residual amounts of fibril interactions, whereas others lack fibril-like content. Generally, Abeta monomers with partially formed fibril-like interactions have the lowest free energies, but their backbone conformations may differ considerably from those in the fibril interior. Overall, Abeta amyloid protofilaments seem to be highly resistant to thermal dissociation. Monomer dissociation from the fibril edge proceeds via multiple stages and pathways. Our simulation findings are discussed in the context of recent experimental results.
我们使用全原子分子动力学方法，研究了温度诱导下β-淀粉样蛋白（Aβ）单体从原纤维原丝上的解离。为了加速构象采样，我们在升高的温度和肽浓度下进行了模拟。通过计算自由能不连通性图，我们绘制了Aβ原纤维表面单体的自由能景观。我们发现，Aβ单体采样了与原纤维具有不同关联程度的各种低自由能状态集。其中一些状态具有原纤维相互作用的残留量，而其他状态则缺乏原纤维样成分。一般来说，具有部分形成的原纤维样相互作用的Aβ单体具有最低的自由能，但其主链构象可能与原纤维内部的构象有很大差异。总体而言，Aβ淀粉样原纤维似乎对热解离具有高度抗性。单体从原纤维边缘的解离通过多个阶段和途径进行。我们在最近的实验结果背景下讨论了模拟结果。
