Sensitivity-enhanced detection of non-labile proton and carbon NMR spectra on water resonances

Novakovic, Mihajlo; Martinho, Ricardo P.; Olsen, Gregory L.; Lustig, Michael; Frydman, Lucio

doi:10.1039/c7cp07046b

Cited by 9 publications

(5 citation statements)

References 45 publications

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“…A theoretical analysis based on a Bloch–McConnell model − shows a similar behavior arising when examining NOESY-based L-PROSY enhancements: Supporting Figure S2 and its associated paragraph show that up to an order of magnitude signal gains are achievable by L-PROSY NOESY, for realistic chemical exchange, cross-relaxation, and longitudinal relaxation rates. Figure illustrates this with data, comparing conventional and L-PROSY NOESY correlations for myo-inositol.…”

Section: Resultsmentioning

confidence: 63%

“…(a) Schematic L-PROSY TOCSY/NOESY sequence, with open shapes corresponding to frequency-selective 90° pulses addressing solely exchangeable sites (here the hydroxyl 1 Hs), defining a t 1 Ramsey modulation that is repeated together with a suitable mixing (delay for NOESY, DIPSI2 for TOCSY) l 1 times. This is followed by a water suppression scheme (flip-back followed by WATERGATE 3919 , or excitation sculpting) and by the detection of all the resonances as a function of t 2 . A two- or four-step phase cycle was used: ϕ 1 = 2( x , – x ), ϕ 2 = 2( x ), 2(− x ), and ϕ R = x ,2(− x ), x .…”

Section: Resultsmentioning

confidence: 99%

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The Incorporation of Labile Protons into Multidimensional NMR Analyses: Glycan Structures Revisited

et al. 2021

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Glycan structures are often stabilized by a repertoire of hydrogen-bonded donor/acceptor groups, revealing longerlived structures that could represent biologically relevant conformations. NMR provides unique data on these hydrogen-bonded networks from multidimensional experiments detecting cross-peaks resulting from through-bond (TOCSY) or through-space (NOESY) interactions. However, fast OH/H 2 O exchange, and the spectral proximity among these NMR resonances, hamper the use of glycans' labile protons in such analyses; consequently, studies are often restricted to aprotic solvents or supercooled aqueous solutions. These nonphysiological conditions may lead to unrepresentative structures or to probing a small subset of accessible conformations that may miss "active" glycan conformations. Looped, projected spectroscopy (L-PROSY) has been recently shown to substantially enhance protein NOESY and TOCSY cross-peaks, for 1 Hs that undergo fast exchange with water. This study shows that even larger enhancements can be obtained for rapidly exchanging OHs in saccharides, leading to the retrieval of previously undetectable 2D TOCSY/NOESY cross-peaks with nonlabile protons. After demonstrating ≥300% signal enhancements on model monosaccharides, these experiments were applied at 1 GHz to elucidate the structural network adopted by a sialic acid homotetramer, used as a model for α,2−8 linked polysaccharides. High-field L-PROSY NMR enabled these studies at higher temperatures and provided insight previously unavailable from lower-field NMR investigations on supercooled samples, involving mostly nonlabile nuclei. Using L-PROSY's NOEs and other restraints, a revised structural model for the homotetramer was obtained combining rigid motifs and flexible segments, that is well represented by conformations derived from 40 μs molecular dynamics simulations.

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Section: Resultsmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 99%

The Incorporation of Labile Protons into Multidimensional NMR Analyses: Glycan Structures Revisited

et al. 2021

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“…Notice that, in contrast to a conventional 2D HSQC-TOCSY experiment where all the polarization that is eventually detected initiates from the 13 Cbound protons, this L-PROSY scheme repeatedly shares the 13 C modulation with the full pool of J HH -coupled protons, which in turn repolarizes back in every block the 13 C-coupled proton from which the t 1 evolution originates. In such sense, this experiment is reminiscent of the Heteronuclear Frequency Label EXchange (HetFLEX) experiment proposed to detect heteronuclear spectra using solvent-driven chemical exchange, 33,34 and to the Fourier-Encoded Saturation Transfer (FEST) experiment relying on 1 H− 1 H spin diffusion to achieve a similar effect in solids. 35 After multiple such repetitions, the modulation imparted by the 13 C on the full proton spin pool becomes significantly enhanced.…”

Section: ■ Introductionmentioning

confidence: 99%

Relaxation-Assisted Magnetization Transfer Phenomena for a Sensitivity-Enhanced 2D NMR

Novakovic,

Kim,

et al. 2023

Anal. Chem.

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2D NOESY and TOCSY play central roles in contemporary NMR. We have recently discussed how solvent-driven exchanges can significantly enhance the sensitivity of such methods when attempting correlations between labile and nonlabile protons. This study explores two scenarios where similar sensitivity enhancements can be achieved in the absence of solvent exchange: the first one involves biomolecular paramagnetic systems, while the other involves small organic molecules in natural abundance. It is shown that, in both cases, the effects introduced by either differential paramagnetic shift and relaxation or by polarization sharing among networks of protons can provide a similar sensitivity boost, as previously discussed for solvent exchange. The origin and potential of the resulting enhancements are analyzed, and experiments that demonstrate them in protein and natural products are exemplified. Limitations and future improvements of these approaches are also briefly discussed.

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“…Measuring and plotting the resulting drop in the resonance of the abundant spins as a function of the RF offset provides a so-called z spectrum of the labile sites, , which is akin to a normal NMR spectrum, but with a dramatically enhanced signal-to-noise ratio (SNR). This leveraging of saturation and chemical exchanges to indirectly map the NMR spectra of dilute sites has led to the generation of numerous solution-state NMR methods that provide SNR enhancements not only for labile sites but also for nonlabile and heteronuclear ones. − Sites of interest that give rise to weak signals as a result of chemical dilution or low natural abundance, or both of these, can thus have their NMR spectra magnified (under suitable conditions) by factors comparable to those obtained by nuclear hyperpolarization.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity Enhancement by Progressive Saturation of the Proton Reservoir: A Solid-State NMR Analogue of Chemical Exchange Saturation Transfer

et al. 2021

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Chemical exchange saturation transfer (CEST) enhances solution-state NMR signals of labile and otherwise invisible chemical sites, by indirectly detecting their signatures as a highly magnified saturation of an abundant resonancefor instance, the 1H resonance of water. Stimulated by this sensitivity magnification, this study presents PROgressive Saturation of the Proton Reservoir (PROSPR), a method for enhancing the NMR sensitivity of dilute heteronuclei in static solids. PROSPR aims at using these heteronuclei to progressively deplete the abundant 1H polarization found in most organic and several inorganic solids, and implements this 1H signal depletion in a manner that reflects the spectral intensities of the heteronuclei as a function of their chemical shifts or quadrupolar offsets. To achieve this, PROSPR uses a looped cross-polarization scheme that repeatedly depletes 1H–1H local dipolar order and then relays this saturation throughout the full 1H reservoir via spin-diffusion processes that act as analogues of chemical exchanges in the CEST experiment. Repeating this cross-polarization/spin-diffusion procedure multiple times results in an effective magnification of each heteronucleus’s response that, when repeated in a frequency-stepped fashion, indirectly maps their NMR spectrum as sizable attenuations of the abundant 1H NMR signal. Experimental PROSPR examples demonstrate that, in this fashion, faithful wideline NMR spectra can be obtained. These 1H-detected heteronuclear NMR spectra can have their sensitivity enhanced by orders of magnitude in comparison to optimized direct-detect experiments targeting unreceptive nuclei at low natural abundance, using modest hardware requirements and conventional NMR equipment at room temperature.

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Sensitivity-enhanced detection of non-labile proton and carbon NMR spectra on water resonances

Cited by 9 publications

References 45 publications

The Incorporation of Labile Protons into Multidimensional NMR Analyses: Glycan Structures Revisited

The Incorporation of Labile Protons into Multidimensional NMR Analyses: Glycan Structures Revisited

Relaxation-Assisted Magnetization Transfer Phenomena for a Sensitivity-Enhanced 2D NMR

Sensitivity Enhancement by Progressive Saturation of the Proton Reservoir: A Solid-State NMR Analogue of Chemical Exchange Saturation Transfer

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