Highly Efficient Polarizing Agents for MAS‐DNP of Proton‐Dense Molecular Solids

Rania Harrabi; Thomas Halbritter; Fabien Aussenac; Ons Dakhlaoui; Johan van Tol; Krishna K. Damodaran; Daniel Lee; Subhradip Paul; Sabine Hediger; Frederic Mentink‐Vigier; Snorri Th Sigurdsson; Gaël De Paëpe

doi:10.1002/anie.202114103

Highly Efficient Polarizing Agents for MAS‐DNP of Proton‐Dense Molecular Solids

Rania Harrabi
, Thomas Halbritter
, Fabien Aussenac
, Ons Dakhlaoui
, Johan van Tol
, Krishna K. Damodaran
, Daniel Lee
, Subhradip Paul
, Sabine Hediger
, Frederic Mentink‐Vigier
, Snorri Th Sigurdsson
, Gaël De Paëpe

University of Iceland

Research output: Contribution to journal › Article › peer-review

Abstract

Efficiently hyperpolarizing proton-dense molecular solids through dynamic nuclear polarization (DNP) solid-state NMR is still an unmet challenge. Polarizing agents (PAs) developed so far do not perform well on proton-rich systems, such as organic microcrystals and biomolecular assemblies. Herein we introduce a new PA, cAsymPol-POK, and report outstanding hyperpolarization efficiency on 12.76 kDa U-¹³C,¹⁵N-labeled LecA protein and pharmaceutical drugs at high magnetic fields (up to 18.8 T) and fast magic angle spinning (MAS) frequencies (up to 40 kHz). The performance of cAsymPol-POK is rationalized by MAS-DNP simulations combined with electron paramagnetic resonance (EPR), density functional theory (DFT) and molecular dynamics (MD). This work shows that this new biradical is compatible with challenging biomolecular applications and unlocks the rapid acquisition of ¹³C–¹³C and ¹⁵N–¹³C correlations of pharmaceutical drugs at natural isotopic abundance, which are key experiments for structure determination.

Original language	Undefined/Unknown
Article number	e202114103
Pages (from-to)	e202114103
Journal	Angewandte Chemie International Edition
Volume	61
Issue number	12
DOIs	https://doi.org/10.1002/anie.202114103
Publication status	Published - 14 Mar 2022

Bibliographical note

Funding Information: This work was supported by the French National Research Agency (CBH‐EUR‐GS and Labex ARCANE ANR‐17‐EURE‐0003, Glyco@Alps ANR‐15‐IDEX‐02, and ANR‐16‐CE11‐0030‐03) and the European Research Council Grant ERC‐CoG‐2015 No. 682895 to G.D.P. Part of this work, carried out on the Platform for Nanocharacterisation (PFNC), was supported by the “Recherches Technologiques de Base” program of the French National Research Agency (ANR). This work was supported by the Icelandic Research Fund, grant No. 173727, and the University of Iceland Research Fund (S.Th.S). T.H. thanks the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (414196920). The National High Magnetic Field Laboratory is supported by the NSF (DMR‐1157490 and DMR‐1644779) and by the State of Florida. The 14.1 T DNP system at NHMFL is funded in part by NIH S10 OD018519 (magnet and console), NSF CHE‐1229170 (gyrotron), and NIH P41GM122698. FMV thanks Shimon Vega for all the discussion related to the Cross‐effect mechanism. Financial support from the TGIR‐RMN‐THC Fr3050 CNRS for conducting DNP experiments at high magnetic fields (18.8 T) is gratefully acknowledged. Funding Information: This work was supported by the French National Research Agency (CBH-EUR-GS and Labex ARCANE ANR-17-EURE-0003, Glyco@Alps ANR-15-IDEX-02, and ANR-16-CE11-0030-03) and the European Research Council Grant ERC-CoG-2015 No. 682895 to G.D.P. Part of this work, carried out on the Platform for Nanocharacterisation (PFNC), was supported by the ?Recherches Technologiques de Base? program of the French National Research Agency (ANR). This work was supported by the Icelandic Research Fund, grant No. 173727, and the University of Iceland Research Fund (S.Th.S). T.H. thanks the Deutsche Forschungsgemeinschaft (DFG) for a postdoctoral fellowship (414196920). The National High Magnetic Field Laboratory is supported by the NSF (DMR-1157490 and DMR-1644779) and by the State of Florida. The 14.1 T DNP system at NHMFL is funded in part by NIH S10 OD018519 (magnet and console), NSF CHE-1229170 (gyrotron), and NIH P41GM122698. FMV thanks Shimon Vega for all the discussion related to the Cross-effect mechanism. Financial support from the TGIR-RMN-THC Fr3050 CNRS for conducting DNP experiments at high magnetic fields (18.8 T) is gratefully acknowledged. Publisher Copyright: © 2022 Wiley-VCH GmbH.

Other keywords

Biomolecules
Dynamic Nuclear Polarization
Electron Spin Resonance Spectroscopy
MAS-DNP
Magnetic Resonance Spectroscopy
Nuclear Magnetic Resonance
Pharmaceutical Preparations
Pharmaceuticals
Polarizing Agents
Protons

Access to Document

10.1002/anie.202114103

Cite this

Harrabi, R., Halbritter, T., Aussenac, F., Dakhlaoui, O., Tol, J. V., Damodaran, K. K., Lee, D., Paul, S., Hediger, S., Mentink‐Vigier, F., Sigurdsson, S. T., & Paëpe, G. D. (2022). Highly Efficient Polarizing Agents for MAS‐DNP of Proton‐Dense Molecular Solids. Angewandte Chemie International Edition, 61(12), e202114103. Article e202114103. https://doi.org/10.1002/anie.202114103

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abstract = "Efficiently hyperpolarizing proton-dense molecular solids through dynamic nuclear polarization (DNP) solid-state NMR is still an unmet challenge. Polarizing agents (PAs) developed so far do not perform well on proton-rich systems, such as organic microcrystals and biomolecular assemblies. Herein we introduce a new PA, cAsymPol-POK, and report outstanding hyperpolarization efficiency on 12.76 kDa U-13C,15N-labeled LecA protein and pharmaceutical drugs at high magnetic fields (up to 18.8 T) and fast magic angle spinning (MAS) frequencies (up to 40 kHz). The performance of cAsymPol-POK is rationalized by MAS-DNP simulations combined with electron paramagnetic resonance (EPR), density functional theory (DFT) and molecular dynamics (MD). This work shows that this new biradical is compatible with challenging biomolecular applications and unlocks the rapid acquisition of 13C–13C and 15N–13C correlations of pharmaceutical drugs at natural isotopic abundance, which are key experiments for structure determination.",

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Harrabi, R, Halbritter, T, Aussenac, F, Dakhlaoui, O, Tol, JV, Damodaran, KK, Lee, D, Paul, S, Hediger, S, Mentink‐Vigier, F, Sigurdsson, ST & Paëpe, GD 2022, 'Highly Efficient Polarizing Agents for MAS‐DNP of Proton‐Dense Molecular Solids', Angewandte Chemie International Edition, vol. 61, no. 12, e202114103, pp. e202114103. https://doi.org/10.1002/anie.202114103

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T1 - Highly Efficient Polarizing Agents for MAS‐DNP of Proton‐Dense Molecular Solids

AU - Harrabi, Rania

AU - Halbritter, Thomas

AU - Aussenac, Fabien

AU - Dakhlaoui, Ons

AU - Tol, Johan van

AU - Damodaran, Krishna K.

AU - Lee, Daniel

AU - Paul, Subhradip

AU - Hediger, Sabine

AU - Mentink‐Vigier, Frederic

AU - Sigurdsson, Snorri Th

AU - Paëpe, Gaël De

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N2 - Efficiently hyperpolarizing proton-dense molecular solids through dynamic nuclear polarization (DNP) solid-state NMR is still an unmet challenge. Polarizing agents (PAs) developed so far do not perform well on proton-rich systems, such as organic microcrystals and biomolecular assemblies. Herein we introduce a new PA, cAsymPol-POK, and report outstanding hyperpolarization efficiency on 12.76 kDa U-13C,15N-labeled LecA protein and pharmaceutical drugs at high magnetic fields (up to 18.8 T) and fast magic angle spinning (MAS) frequencies (up to 40 kHz). The performance of cAsymPol-POK is rationalized by MAS-DNP simulations combined with electron paramagnetic resonance (EPR), density functional theory (DFT) and molecular dynamics (MD). This work shows that this new biradical is compatible with challenging biomolecular applications and unlocks the rapid acquisition of 13C–13C and 15N–13C correlations of pharmaceutical drugs at natural isotopic abundance, which are key experiments for structure determination.

AB - Efficiently hyperpolarizing proton-dense molecular solids through dynamic nuclear polarization (DNP) solid-state NMR is still an unmet challenge. Polarizing agents (PAs) developed so far do not perform well on proton-rich systems, such as organic microcrystals and biomolecular assemblies. Herein we introduce a new PA, cAsymPol-POK, and report outstanding hyperpolarization efficiency on 12.76 kDa U-13C,15N-labeled LecA protein and pharmaceutical drugs at high magnetic fields (up to 18.8 T) and fast magic angle spinning (MAS) frequencies (up to 40 kHz). The performance of cAsymPol-POK is rationalized by MAS-DNP simulations combined with electron paramagnetic resonance (EPR), density functional theory (DFT) and molecular dynamics (MD). This work shows that this new biradical is compatible with challenging biomolecular applications and unlocks the rapid acquisition of 13C–13C and 15N–13C correlations of pharmaceutical drugs at natural isotopic abundance, which are key experiments for structure determination.

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KW - Electron Spin Resonance Spectroscopy

KW - MAS-DNP

KW - Magnetic Resonance Spectroscopy

KW - Nuclear Magnetic Resonance

KW - Pharmaceutical Preparations

KW - Pharmaceuticals

KW - Polarizing Agents

KW - Protons

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U2 - 10.1002/anie.202114103

DO - 10.1002/anie.202114103

M3 - Grein

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JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

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