Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , Shenzhen, 518055, China.
J Chem Theory Comput. 2017 Nov 14;13(11):5731-5744. doi: 10.1021/acs.jctc.7b00803. Epub 2017 Oct 27.
Early oligomerization during amyloid-β (Aβ) aggregation is essential for Aβ neurotoxicity. Understanding how unstructured Aβs assemble into oligomers, especially those rich in β-sheets, is essential but remains challenging as the assembly process is too transient for experimental characterization and too slow for molecular dynamics simulations. So far, atomic simulations are limited only to studies of either oligomer structures or assembly pathways for short Aβ segments. To overcome the computational challenge, we combine in this study a hybrid-resolution model and adaptive sampling techniques to perform over 2.7 ms of simulations of formation of full-length Aβ40 dimers that are the earliest toxic oligomeric species. The Markov state model is further employed to characterize the transition pathways and associated kinetics. Our results show that for two major forms of β-sheet-rich structures reported experimentally, the corresponding assembly mechanisms are markedly different. Hairpin-containing structures are formed by direct binding of soluble Aβ in β-hairpin-like conformations. Formation of parallel, in-register structures resembling fibrils occurs ∼100-fold more slowly and involves a rapid encounter of Aβ in arbitrary conformations followed by a slow structural conversion. The structural conversion proceeds via diverse pathways but always requires transient unfolding of encounter complexes. We find that the transition kinetics could be affected differently by intra-/intermolecular interactions involving individual residues in a conformation-dependent manner. In particular, the interactions involving Aβ's N-terminal part promote the assembly into hairpin-containing structures but delay the formation of fibril-like structures, thus explaining puzzling observations reported previously regarding the roles of this region in the early assembly process.
早期淀粉样蛋白-β（Aβ）聚集过程中的寡聚化对于 Aβ 的神经毒性至关重要。了解无规卷曲的 Aβ 如何组装成寡聚体，尤其是富含β-折叠的寡聚体，这一点至关重要，但由于组装过程过于短暂而无法进行实验表征，且分子动力学模拟又过于缓慢，因此仍然具有挑战性。到目前为止，原子模拟仅限于研究寡聚体结构或短 Aβ 片段的组装途径。为了克服计算上的挑战，我们在这项研究中结合了混合分辨率模型和自适应采样技术，对全长 Aβ40 二聚体的形成过程进行了超过 2.7 毫秒的模拟，Aβ40 二聚体是最早出现的毒性寡聚体。进一步采用马尔可夫状态模型来描述过渡途径和相关的动力学。我们的结果表明，对于实验中报道的两种主要的富含β-折叠结构形式，相应的组装机制明显不同。含有发夹结构的是通过可溶性 Aβ 在β-发夹样构象中的直接结合形成的。平行、共面的结构类似于原纤维的形成速度要慢约 100 倍，涉及任意构象的 Aβ 的快速相遇，然后是缓慢的结构转换。结构转换通过多种途径进行，但始终需要构象相遇复合物的瞬时展开。我们发现，构象依赖性的单个残基的分子内/分子间相互作用可以以不同的方式影响转变动力学。特别是涉及 Aβ 的 N 端部分的相互作用促进了含有发夹结构的组装，但延迟了原纤维样结构的形成，从而解释了以前关于该区域在早期组装过程中的作用的令人费解的观察结果。
