The N-Terminal Domain of Aβ40-Amyloid Fibril: The MOMD Perspective of its Dynamic Structure from NMR Lineshape Analysis

Eva Meirovitch, Zhichun Liang, Jack H. Freed

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

We have developed the stochastic microscopic-order-macroscopic-disorder (MOMD) approach for elucidating dynamic structures in the solid-state from 2H NMR lineshapes. In MOMD, the probe experiences an effective/collective motional mode. The latter is described by a potential, u, which represents the local spatial-restrictions, a local-motional diffusion tensor, R, 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 Aβ40-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.

Original languageEnglish
Pages (from-to)1202-1211
Number of pages10
JournalJournal of Physical Chemistry B
Volume126
Issue number6
DOIs
StatePublished - 17 Feb 2022

Bibliographical note

Publisher Copyright:
© 2022 American Chemical Society

Fingerprint

Dive into the research topics of 'The N-Terminal Domain of Aβ40-Amyloid Fibril: The MOMD Perspective of its Dynamic Structure from NMR Lineshape Analysis'. Together they form a unique fingerprint.

Cite this