Abstract
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.
Highlights
Chemical exchange saturation transfer (CEST)[1] is an approach that can dramatically enhance the NMR sensitivity of nuclei in sites undergoing chemical exchange and has opened up numerous applications in solution-state magnetic resonance.[2−6] CEST amplifies the signatures of labile protons in metabolites and biomacromolecules by up to 3 orders of magnitude, leading to unprecedented imaging possibilities and providing a unique source of metabolic in vivo MRI contrast.[7−12] CEST enables the detection of invisible structural conformation states in the solution NMR of nucleic acids[13,14] and proteins,[15−18] the observation of transient reaction intermediates,[19] and the enhancement of structurally relevant cross peaks in multidimensional correlation NMR measurements.[20,21]
CEST magnifies the weak response from dilute chemical sites by repeatedly saturating their spin polarization using a weak radio frequency (RF) field and relying on chemical exchanges to pass this information to an abundant spin pool with a much stronger NMR resonance, which can report on the dilute spins’ spectrum with a substantial sensitivity enhancement
Heteronuclear decoupling during the encoding of the heteronuclear NMR spectrum. These effects and their implications for measuring accurate NMR line shapes are further analyzed in Supplements 4 and 5 in the SI. These results illustrate the potential for using CEST-inspired concepts for enhancing the solid-state NMR detectability of unreceptive, dilute heteronuclei
Summary
Chemical exchange saturation transfer (CEST)[1] is an approach that can dramatically enhance the NMR sensitivity of nuclei in sites undergoing chemical exchange and has opened up numerous applications in solution-state magnetic resonance.[2−6] CEST amplifies the signatures of labile protons in metabolites and biomacromolecules by up to 3 orders of magnitude, leading to unprecedented imaging possibilities and providing a unique source of metabolic in vivo MRI contrast.[7−12] CEST enables the detection of invisible structural conformation states in the solution NMR of nucleic acids[13,14] and proteins,[15−18] the observation of transient reaction intermediates,[19] and the enhancement of structurally relevant cross peaks in multidimensional correlation NMR measurements.[20,21] CEST magnifies the weak response from dilute chemical sites by repeatedly saturating their spin polarization using a weak radio frequency (RF) field and relying on chemical exchanges to pass this information to an abundant spin pool with a much stronger NMR resonance, which can report on the dilute spins’ spectrum with a substantial sensitivity enhancement. 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,[22,23] 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
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