Journal
JOURNAL OF MAGNETIC RESONANCE
Volume 294, Issue -, Pages 169-180Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.jmr.2018.07.010
Keywords
NOESY; TOCSY; Sensitivity enhancement; Zeno effect; Looped projective measurements; Structure elucidations
Funding
- Kimmel Institute for Magnetic Resonance (Weizmann Institute)
- EU [642773]
- Blythe Brenden-Mann New Scientist Fund
- Azrieli Foundation
- French Foreign Service
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Cross-relaxation and isotropic mixing phenomena leading to the Nuclear Overhauser Effect (NOE) and to the TOCSY experiment, lie at the center of structural determinations by NMR. 2D TOCSY and NOESY exploit these polarization transfer effects to determine inter-site connectivities and molecular geometries under physiologically-relevant conditions. Among these sequences' drawback, particularly for the case of NOEs, are a lack of sensitivity arising from small structurally-relevant cross peaks. The present study explores the application of multiple Zeno-like projective measurements, to enhance the cross-peaks between spectrally distinct groups in proteins-in particular between amide and aliphatic protons. The enhancement is based on repeating the projection done by Ramsey or TOCSY blocks multiple times, in what we refer to as Looped, PROjected Spectroscopy (L-PROSY). This leads to a reset of the amide/aliphatic transfer processes; the initial slopes of the NOE- or J-transfer effects thus define the cross-peak growth, and a faster cross-peak buildup is achieved upon looping these transfers over the allotted time T-1. These projections also help to better preserve the magnetization originating in the amides, resulting in an overall improvement in sensitivity. L-PROSY's usefulness is demonstrated by incorporating it into two widely used protein NMR experiments: 2D N-15-H-1 HMQC-NOESY and N-15-filtered 2D NOESY. Different parameters dictating the overall SNR improvement, particularly the protein correlation times and the amide-water chemical exchange rates, were examined, and L-PROSY's enhancements resulted for all tested proteins. The largest cross-peak enhancements were observed for unstructured proteins, where chemical exchanges with the solvent of the kind that tend to average out NOE cross-peaks in conventional NMR, boost L-PROSY's cross-peaks by replenishing the amide's magnetizations within each loop. Enhanced cross-peaks were also found in extensions involving TOCSY-based experiments when applied to proteins with unfolded segments. (C) 2018 Elsevier Inc. All rights reserved.
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