Atomic Structure of GNNQQNY Nanocrystals: A Validated Approach for Polymorphic Amyloids
Name
chemrxiv-2025-70r6v.pdf
Description
Accepted version
Size
1.01 MB
Format
Adobe PDF
Checksum (MD5)
7ddd4ae28b637cb311f89a797f4b3265
Author(s)
Mishra, Aditya
Palani, Ravi S
Griffin, Robert G
Date Issued
December 15, 2025
Journal
The Journal of Physical Chemistry Letters
Publisher
American Chemical Society
Citation
Atomic Structure of GNNQQNY Nanocrystals: A Validated Approach for Polymorphic Amyloids. Aditya Mishra, Ravi S. Palani, and Robert G. Griffin. The Journal of Physical Chemistry Letters 2025 16 (51), 13155-13161.
Version
Author's final manuscript
Abstract
Solid-state Nuclear Magnetic Resonance (ssNMR) is a powerful tool for determining the structures
of complex biological systems like amyloid fibrils, which are often challenging to study due to
polymorphism. However, traditional ssNMR techniques are often limited by low signal-to-noise ratios
(SNR) for long-range distances and by spectral overlap in degenerate systems. Here, we establish a
approach to address these challenges using the amyloid heptapeptide GNNQQNY, an ideal model for
studying polymorphism due to its ability to assemble into either crystals or fibrils depending on preparation
conditions. By employing specific 13C, 15N-labeling to resolve spectral degeneracy, we obtained numerous
high precision distance restraints using frequency selective rotational echo double resonance (FSR) and
z-filtered transfer echo double resonance (ZF-TEDOR) experiments. These restraints enabled us to
calculate the high-resolution ssNMR structure of GNNQQNY nanocrystals, which closely matches the
known X-ray crystal structure, thus validating our approach. Anticipating severe spectral degeneracies in
studying polymorphic fibrils, we also introduce a novel FSR-RFDR pulse sequence which effectively
deconvolves overlapped resonances, enabling precise distance measurements even in complex spectra.
Our validated method, which includes specific labeling and the FSR-RFDR sequence, establishes a robust
pipeline for future structural studies of heterogeneous amyloid fibrils, advancing our understanding of
polymorphism at the atomic level.
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DOI of Published Version
https://doi.org/10.1021/acs.jpclett.5c03245
