Baker Laboratory of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853-1301, United States.
ACS Chem Neurosci. 2017 Jan 18;8(1):201-209. doi: 10.1021/acschemneuro.6b00331. Epub 2016 Nov 18.
Fibrils formed by the β-amyloid (Aβ) peptide play a central role in the development of Alzheimer's disease. In this study, the principles governing their growth and stability are investigated by analyzing canonical and replica-exchange molecular dynamics trajectories of Aβ fibrils. In particular, an unstructured monomer was allowed to interact freely with an Aβ fibril template. Trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue and principal components, respectively, were analyzed. Also, thermal unbinding (unfolding) of an Aβ peptide from the fibril template was investigated. These analyses enable us to illustrate the entire process of Aβ fibril elongation and to elucidate the key residues involved in it. Several different pathways were identified during the search for the fibril conformation by the monomer, which finally follows a dock-lock mechanism with two distinct locking stages. However, it was found that the correct binding, with native hydrogen bonds, of the free monomer to the fibril template at both stages is crucial for fibril elongation. In other words, if the monomer is incorrectly bound (with nonnative hydrogen bonds) to the fibril template during the first "docking" stage, it can remain attached to it for a long time before it dissociates and either attempts a different binding or allows another monomer to bind. This finding is consistent with an experimentally observed "stop-and-go" mechanism of fibril growth.
β-淀粉样蛋白（Aβ）肽形成的原纤维在阿尔茨海默病的发展中起着核心作用。在这项研究中，通过分析 Aβ原纤维的典型和复制交换分子动力学轨迹，研究了它们生长和稳定性的原理。特别是，允许无结构单体与 Aβ原纤维模板自由相互作用。使用粗粒度联合残基力场生成轨迹，并分别沿着每个残基的主链虚拟键角θ和主链虚拟键二面角γ以及主成分分析一维和二维自由能景观（FEL）。此外，还研究了 Aβ肽从原纤维模板的热解吸（解折叠）。这些分析使我们能够说明 Aβ原纤维伸长的整个过程，并阐明参与其中的关键残基。在单体寻找原纤维构象的过程中，确定了几种不同的途径，最终遵循带有两个不同锁定阶段的对接锁定机制。然而，发现单体与原纤维模板以天然氢键正确结合对于原纤维伸长至关重要。换句话说，如果单体在第一“对接”阶段与原纤维模板不正确结合（具有非天然氢键），它可以在解离之前长时间附着在其上，然后要么尝试不同的结合，要么允许另一个单体结合。这一发现与实验观察到的原纤维生长的“停止-前进”机制一致。
