skip to main content


Title: Highly Efficient Polarizing Agents for MAS‐DNP of Proton‐Dense Molecular Solids
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 of13C–13C and15N–13C correlations of pharmaceutical drugs at natural isotopic abundance, which are key experiments for structure determination.

 
more » « less
NSF-PAR ID:
10368012
Author(s) / Creator(s):
 ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  ;  
Publisher / Repository:
Wiley Blackwell (John Wiley & Sons)
Date Published:
Journal Name:
Angewandte Chemie
Volume:
134
Issue:
12
ISSN:
0044-8249
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. 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 of13C–13C and15N–13C correlations of pharmaceutical drugs at natural isotopic abundance, which are key experiments for structure determination.

     
    more » « less
  2. Abstract

    We report dissolution Dynamic Nuclear Polarization (d‐DNP) of [15N3]metronidazole ([15N3]MNZ) for the first time. Metronidazole is a clinically approved antibiotic, which can be potentially employed as a hypoxia‐sensing molecular probe using15N hyperpolarized (HP) nucleus. The DNP process is very efficient for [15N3]MNZ with an exponential build‐up constant of 13.8 min using trityl radical. After dissolution and sample transfer to a nearby 4.7 T Magnetic Resonance Imaging scanner, HP [15N3]MNZ lasted remarkably long with T1values up to 343 s and15N polarizations up to 6.4 %. A time series of HP [15N3]MNZ images was acquired in vitro using a steady state free precession sequence on the15NO2peak. The signal lasted over 13 min with notably long T2of 20.5 s. HP [15N3]MNZ was injected in the tail vein of a healthy rat, and dynamic spectroscopy was performed over the rat brain. The in vivo HP15N signals persisted over 70 s, demonstrating an unprecedented opportunity for in vivo studies.

     
    more » « less
  3. Abstract

    We report dissolution Dynamic Nuclear Polarization (d‐DNP) of [15N3]metronidazole ([15N3]MNZ) for the first time. Metronidazole is a clinically approved antibiotic, which can be potentially employed as a hypoxia‐sensing molecular probe using15N hyperpolarized (HP) nucleus. The DNP process is very efficient for [15N3]MNZ with an exponential build‐up constant of 13.8 min using trityl radical. After dissolution and sample transfer to a nearby 4.7 T Magnetic Resonance Imaging scanner, HP [15N3]MNZ lasted remarkably long with T1values up to 343 s and15N polarizations up to 6.4 %. A time series of HP [15N3]MNZ images was acquired in vitro using a steady state free precession sequence on the15NO2peak. The signal lasted over 13 min with notably long T2of 20.5 s. HP [15N3]MNZ was injected in the tail vein of a healthy rat, and dynamic spectroscopy was performed over the rat brain. The in vivo HP15N signals persisted over 70 s, demonstrating an unprecedented opportunity for in vivo studies.

     
    more » « less
  4. Abstract

    Dynamic nuclear polarization (DNP) increases NMR sensitivity by transferring polarization from electron to nuclear spins. Herein, we demonstrate that electron decoupling with chirped microwave pulses enables improved observation of DNP‐enhanced13C spins in direct dipolar contact with electron spins, thereby leading to an optimal delay between transients largely governed by relatively fast electron relaxation. We report the first measurement of electron longitudinal relaxation time (T1e) during magic angle spinning (MAS) NMR by observation of DNP‐enhanced NMR signals (T1e=40±6 ms, 40 mMtrityl, 4.0 kHz MAS, 4.3 K). With a 5 ms DNP period, electron decoupling results in a 195 % increase in signal intensity. MAS at 4.3 K, DNP, electron decoupling, and short recycle delays improve the sensitivity of13C in the vicinity of the polarizing agent. This is the first demonstration of recovery times between MAS‐NMR transients being governed by short electron T1and fast DNP transfer.

     
    more » « less
  5. Abstract

    Dynamic nuclear polarization (DNP) increases NMR sensitivity by transferring polarization from electron to nuclear spins. Herein, we demonstrate that electron decoupling with chirped microwave pulses enables improved observation of DNP‐enhanced13C spins in direct dipolar contact with electron spins, thereby leading to an optimal delay between transients largely governed by relatively fast electron relaxation. We report the first measurement of electron longitudinal relaxation time (T1e) during magic angle spinning (MAS) NMR by observation of DNP‐enhanced NMR signals (T1e=40±6 ms, 40 mMtrityl, 4.0 kHz MAS, 4.3 K). With a 5 ms DNP period, electron decoupling results in a 195 % increase in signal intensity. MAS at 4.3 K, DNP, electron decoupling, and short recycle delays improve the sensitivity of13C in the vicinity of the polarizing agent. This is the first demonstration of recovery times between MAS‐NMR transients being governed by short electron T1and fast DNP transfer.

     
    more » « less