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1H detection and dynamic nuclear polarization–enhanced NMR of Aβ1-42 fibrils

Bahri, Salima ; Silvers, Robert ; Michael, Brian ; Jaudzems, Kristaps ; Lalli, Daniela ; Casano, Gilles ; Ouari, Olivier ; Lesage, Anne ; Pintacuda, Guido and Linse, Sara LU , et al. (2022) In Proceedings of the National Academy of Sciences of the United States of America 119(1).
Abstract

Several publications describing high-resolution structures of amyloid-β (Aβ) and other fibrils have demonstrated that magic-angle spinning (MAS) NMR spectroscopy is an ideal tool for studying amyloids at atomic resolution. Nonetheless, MAS NMR suffers from low sensitivity, requiring relatively large amounts of samples and extensive signal acquisition periods, which in turn limits the questions that can be addressed by atomic-level spectroscopic studies. Here, we show that these drawbacks are removed by utilizing two relatively recent additions to the repertoire of MAS NMR experiments—namely, 1H detection and dynamic nuclear polarization (DNP). We show resolved and sensitive two-dimensional (2D) and three-dimensional (3D)... (More)

Several publications describing high-resolution structures of amyloid-β (Aβ) and other fibrils have demonstrated that magic-angle spinning (MAS) NMR spectroscopy is an ideal tool for studying amyloids at atomic resolution. Nonetheless, MAS NMR suffers from low sensitivity, requiring relatively large amounts of samples and extensive signal acquisition periods, which in turn limits the questions that can be addressed by atomic-level spectroscopic studies. Here, we show that these drawbacks are removed by utilizing two relatively recent additions to the repertoire of MAS NMR experiments—namely, 1H detection and dynamic nuclear polarization (DNP). We show resolved and sensitive two-dimensional (2D) and three-dimensional (3D) correlations obtained on 13C,15N-enriched, and fully protonated samples of M01-42 fibrils by high-field 1H-detected NMR at 23.4 T and 18.8 T, and 13C-detected DNP MAS NMR at 18.8 T. These spectra enable nearly complete resonance assignment of the core of M01-42 (K16-A42) using submilligram sample quantities, as well as the detection of numerous unambiguous internuclear proximities defining both the structure of the core and the arrangement of the different monomers. An estimate of the sensitivity of the two approaches indicates that the DNP experiments are currently ∼6.5 times more sensitive than 1H detection. These results suggest that 1H detection and DNP may be the spectroscopic approaches of choice for future studies of Aβ and other amyloid systems.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
H detection, Amyloid β, Dynamic nuclear polarization, Magic-angle spinning
in
Proceedings of the National Academy of Sciences of the United States of America
volume
119
issue
1
article number
e2114413119
publisher
National Academy of Sciences
external identifiers
  • pmid:34969859
  • scopus:85122687080
ISSN
0027-8424
DOI
10.1073/pnas.2114413119
language
English
LU publication?
yes
id
9e0ce1fd-4c27-45a1-b6ed-b68e55552c7e
date added to LUP
2022-02-28 14:29:19
date last changed
2024-03-16 12:40:48
@article{9e0ce1fd-4c27-45a1-b6ed-b68e55552c7e,
  abstract     = {{<p>Several publications describing high-resolution structures of amyloid-β (Aβ) and other fibrils have demonstrated that magic-angle spinning (MAS) NMR spectroscopy is an ideal tool for studying amyloids at atomic resolution. Nonetheless, MAS NMR suffers from low sensitivity, requiring relatively large amounts of samples and extensive signal acquisition periods, which in turn limits the questions that can be addressed by atomic-level spectroscopic studies. Here, we show that these drawbacks are removed by utilizing two relatively recent additions to the repertoire of MAS NMR experiments—namely, <sup>1</sup>H detection and dynamic nuclear polarization (DNP). We show resolved and sensitive two-dimensional (2D) and three-dimensional (3D) correlations obtained on <sup>13</sup>C,<sup>15</sup>N-enriched, and fully protonated samples of M<sub>0</sub>Aβ<sub>1-42</sub> fibrils by high-field <sup>1</sup>H-detected NMR at 23.4 T and 18.8 T, and <sup>13</sup>C-detected DNP MAS NMR at 18.8 T. These spectra enable nearly complete resonance assignment of the core of M<sub>0</sub>Aβ<sub>1-42</sub> (K16-A42) using submilligram sample quantities, as well as the detection of numerous unambiguous internuclear proximities defining both the structure of the core and the arrangement of the different monomers. An estimate of the sensitivity of the two approaches indicates that the DNP experiments are currently ∼6.5 times more sensitive than <sup>1</sup>H detection. These results suggest that <sup>1</sup>H detection and DNP may be the spectroscopic approaches of choice for future studies of Aβ and other amyloid systems.</p>}},
  author       = {{Bahri, Salima and Silvers, Robert and Michael, Brian and Jaudzems, Kristaps and Lalli, Daniela and Casano, Gilles and Ouari, Olivier and Lesage, Anne and Pintacuda, Guido and Linse, Sara and Griffin, Robert G.}},
  issn         = {{0027-8424}},
  keywords     = {{H detection; Amyloid β; Dynamic nuclear polarization; Magic-angle spinning}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{National Academy of Sciences}},
  series       = {{Proceedings of the National Academy of Sciences of the United States of America}},
  title        = {{<sup>1</sup>H detection and dynamic nuclear polarization–enhanced NMR of Aβ<sub>1-42</sub> fibrils}},
  url          = {{http://dx.doi.org/10.1073/pnas.2114413119}},
  doi          = {{10.1073/pnas.2114413119}},
  volume       = {{119}},
  year         = {{2022}},
}