The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900 Israel.
Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, United States.
J Phys Chem B. 2022 Feb 17;126(6):1202-1211. doi: 10.1021/acs.jpcb.1c10131. Epub 2022 Feb 5.
We have developed the stochastic microscopic-order-macroscopic-disorder (MOMD) approach for elucidating dynamic structures in the solid-state from H NMR lineshapes. In MOMD, the probe experiences an effective/collective motional mode. The latter is described by a potential, , which represents the local spatial-restrictions, a local-motional diffusion tensor, , and key features of local geometry. Previously we applied MOMD to the well-structured core domain of the 3-fold-symmetric twisted polymorph of the Aβ-amyloid fibril. Here, we apply it to the N-terminal domain of this fibril. We find that the dynamic structures of the two domains are largely similar but differ in the magnitude and complexity of the key physical parameters. This interpretation differs from previous multisimple-mode (MSM) interpretations of the same experimental data. MSM used for the two domains different combinations of simple motional modes taken to be independent. For the core domain, MOMD and MSM disagree on the character of the dynamic structure. For the N-terminal domain, they even disagree on whether this chain segment is structurally ordered (MOMD finds that it is), and whether it undergoes a phase transition at 260 K where bulklike water located in the fibril matrix freezes (MOMD finds that it does not). These are major differences associated with an important system. While the MOMD description is a physically sound one, there are drawbacks in the MSM descriptions. The results obtained in this study promote our understanding of the dynamic structure of protein aggregates. Thus, they contribute to the effort to pharmacologically control neurodegenerative disorders believed to be caused by such aggregates.
我们开发了随机微观-宏观-无序（MOMD）方法，从 H NMR 线宽图中阐明固态中的动态结构。在 MOMD 中，探针经历有效/集体运动模式。后者由势能表示，代表局部空间限制、局部运动扩散张量和局部几何的关键特征。以前，我们将 MOMD 应用于 3 重对称扭曲多晶态 Aβ-淀粉样纤维核心域。在这里，我们将其应用于该纤维的 N 端域。我们发现两个域的动态结构在很大程度上相似，但关键物理参数的大小和复杂性不同。这种解释与以前对相同实验数据的多简单模式（MSM）解释不同。MSM 用于两个域不同的简单运动模式组合，认为它们是独立的。对于核心域，MOMD 和 MSM 对动态结构的特征存在分歧。对于 N 端域，它们甚至在该链段是否具有结构有序性（MOMD 发现它是）以及在 260 K 时是否发生相变，即位于纤维基质中的类似块状水是否冻结（MOMD 发现它没有）方面存在分歧。这些是与重要系统相关的主要差异。虽然 MOMD 描述是合理的，但 MSM 描述存在缺陷。本研究的结果促进了我们对蛋白质聚集体动态结构的理解。因此，它们有助于控制被认为由此类聚集体引起的神经退行性疾病的药理学努力。
