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A continuing priority is to better understand and resolve the barriers to using nonuniform sampling (NUS) in challenging small molecule 2D NMR with subsampling of the Nyquist grid (a.k.a. coverage) below 50%. Possible causes for artifacts, often termed sampling noise, in 1D‐NUS of 2D‐NMR are revisited here, where weak aliasing artifacts are a growing concern as NUS becomes sparser. As NUS schedules become sparser, repeat sequences are shown to occur in the dense sampling regions early in the sampling schedule, causing aliasing artifacts in resulting spectra. An intuitive screening approach that detects patterns in sampling schedules based on a convolutional filter was implemented. Sampling schedules that have low proportions of repeat sequences show significantly reduced artifacts. Another route to remediate early repeat sequences is a short period of uniform sampling at the beginning of the schedule, which also leads to a significant suppression of unwanted sampling noise. Combining the repeat sequence filter with a survey of HSQC and LR‐HSQMBC experiments, it is shown that very short initial uniform regions of about 2%–4% of the sampling space can ameliorate repeat sequences in sparser NUS and lead to robust spectral reconstructions by iterative soft thresholding (IST), even when the point spread function is unchanged. Using the principles developed here, a suite of 'one‐click' schedules was developed for broader use. [ABSTRACT FROM AUTHOR]

Recent developments in para‐hydrogen‐induced polarization (PHIP) methods allow the nuclear magnetic resonance (NMR) detection of specific classes of compounds, down to sub‐micromolar concentration in solution. However, when dealing with complex mixtures, signal resolution requires the acquisition of 2D PHIP‐NMR spectra, which often results in long experimental times. This strongly limits the applicability of these 2D PHIP‐NMR techniques in areas in which high‐throughput analysis is required. Here, we present a combination of fast acquisition and nonuniform sampling that can afford a 10‐fold reduction in measuring time without compromising the spectral quality. This approach was tested on a mixture of substrates at micromolar concentration, for which a resolved 2D PHIP spectrum was acquired in less than 3 min. [ABSTRACT FROM AUTHOR]

In this work, we discuss representative examples of the application of nonuniform sampling (NUS) in small‐molecule structure determination in a pharmaceutical research and development and quality control setting. We demonstrate the advantages of NUS over traditional sampling in various industrial applications of nuclear magnetic resonance (NMR). We propose an optimal trade‐off between the quality and the time efficiency of 'routine' measurements, as demonstrated via a test sample of vinpocetine analyzed on a 'work horse' NMR spectrometer. In addition, we present case studies where the application of NUS contributed significantly to the successful completion of some challenging structure determination task at hand. To that end, in some cases, we combined NUS with a method of decoupling in the indirect dimension that gives 'constant time' nuclear Overhauser effect spectroscopy (NOESY) and 'constant time' heteronuclear multiple bond correlation (HMBC) spectra. NUS proved to be superior over traditional sampling even for the analysis of trace impurities, where the need to cope with a thousand‐fold or even larger dynamic range and low signal‐to‐noise ratio for the impurity signals is quite a challenge. [ABSTRACT FROM AUTHOR]

An important step in the process of protein research by NMR is the assignment of chemical shifts. In the coat protein of IKe bacteriophage, there are 53 residues making up a long helix resulting in relatively high spectral ambiguity. Assignment thus requires the collection of a set of three‐dimensional (3D) experiments and the preparation of sparsely labeled samples. Increasing the dimensionality can facilitate fast and reliable assignment of IKe and of larger proteins. Recent progress in nonuniform sampling techniques made the application of multidimensional NMR solid‐state experiments beyond 3D more practical. 4D 1H‐detected experiments have been demonstrated in high‐fields and at spinning speeds of 60 kHz and higher but are not practical at spinning speeds of 10–20 kHz for fully protonated proteins. Here, we demonstrate the applicability of a nonuniformly sampled 4D 13C/15N‐only correlation experiment performed at a moderate field of 14.1 T, which can incorporate sufficiently long acquisition periods in all dimensions. We show how a single CANCOCX experiment, supported by several 2D carbon‐based correlation experiments, is utilized for the assignment of heteronuclei in the coat protein of the IKe bacteriophage. One sparsely labeled sample was used to validate sidechain assignment of several hydrophobic‐residue sidechains. A comparison to solution NMR studies of isolated IKe coat proteins embedded in micelles points to key residues involved in structural rearrangement of the capsid upon assembly of the virus. The benefits of 4D to a quicker assignment are discussed, and the method may prove useful for studying proteins at relatively low fields. [ABSTRACT FROM AUTHOR]

Monitoring of chemical reactions is best carried out using methods that sample the test object at a rate greater than the time scale of the processes taking place. The recently proposed time‐resolved nonuniform sampling (TR‐NUS) method allows the use of two‐dimensional (2D) nuclear magnetic resonance (NMR) spectra for this purpose and provides a time resolution equivalent to that achievable using one‐dimensional spectra. Herein, we show that TR‐NUS acquired data eliminates 2D spectral line disturbances and enables more accurate signal integration and kinetics conclusions. The considerations are exemplified with a seemingly simple aza‐Michael reaction of benzylamine and acrylamide. Surprisingly, the product identification is possible only using 2D spectra, although credible monitoring requires TR‐NUS. [ABSTRACT FROM AUTHOR]

Nonuniform sampling (NUS) of multidimensional NMR experiments is a powerful tool to obtain high‐resolution spectra with less instrument time. With NUS, only a subset of the points needed for conventional Fourier transformation is recorded, and sophisticated algorithms are needed to reconstruct the missing data points. During the last decade, several software packages implementing the reconstruction algorithms have emerged and been refined and now result in spectra of almost similar quality as spectra from conventionally recorded and processed data. However, from the number of literature references to the reconstruction methods, many more multidimensional NMR spectra could presumably be recorded with NUS. To help researchers considering to start using NUS for their NMR experiments, we here review 13 different reconstruction methods found in five software packages (CambridgeCS, hmsIST, MddNMR, NESTA‐NMR, and SMILE). We have compared how the methods run with the provided example scripts for reconstructing a nonuniform sampled three‐dimensional 15N–NOESY–HSQC at sampling densities from 5% to 50%. Overall, the spectra are all of similar quality above 20% sampling density. Thus, without any particular knowledge about the details of the reconstruction algorithms, significant reduction in the experiment time can be achieved. Below 20% sampling density, the intensities of particular weak peaks start being affected. MddNMR's IST with virtual echo and the SMILE algorithms still reproduced the spectra with the highest accuracy of peak intensities. [ABSTRACT FROM AUTHOR]

The number circled in green originally listed as a 2 as seen in the left figure, was a typo, possibly because the prior number was a 2, which was accidentally repeated. Cullen, L. E., Marchiori, A., Rovnyak, D., Magn Reson Chem 2023, 61 (9-10), 337. https://doi.org/10.1002/mrc.5340 Explanation of typo in Figure S1 panel (a) for editorial review: For comparison, the original is left and the corrected is right. Correction to "Revisiting aliasing noise to build more robust sparsity in nonuniform sampling 2D-NMR". [Extracted from the article]

Nonuniform sampling (NUS) strategies are developed for acquiring highly resolved 1,1-ADEQUATE spectra, in both conventional and homodecoupled (HD) variants with improved sensitivity. Specifically, the quantile-directed and Poisson gap methods were critically compared for distributing the samples nonuniformly, and the quantile schedules were further optimized for weighting. Both maximum entropy and iterative soft thresholding spectral estimation algorithms were evaluated. All NUS approaches were robust when the degree of data reduction is moderate, on the order of a 50% reduction of sampling points. Further sampling reduction by NUS is facilitated by using weighted schedules designed by the quantile method, which also suppresses sampling noise well. Seed independence and the ability to specify the sample weighting in quantile scheduling are important in optimizing NUS for 1,1-ADEQUATE data acquisition. Using NUS yields an improvement in sensitivity, while also making longer evolution times accessible that would be difficult or impractical to attain by uniform sampling. Theoretical predictions for the sensitivity enhancements in these experiments are in the range of 5-20%; NUS is shown to disambiguate weak signals, reveal some nJCC correlations obscured by noise, and improve signal strength relative to uniform sampling in the same experimental time. This work presents sample schedule development for applying NUS to challenging experiments. The schedules developed here are made available for general use and should facilitate the broader utilization of ADEQUATE experiments (including 1,1-, 1,n-, and HD- variants) for challenging structure elucidation problems. [ABSTRACT FROM AUTHOR]

Nuclear magnetic resonance (NMR) is a well‐known analytical technique for the analysis of complex mixtures. Its quantitative capability makes it ideally suited to metabolomics or lipidomics studies involving large sample collections of complex biological samples. To overcome the ubiquitous limitation of spectral overcrowding when recording 1D NMR spectra on such samples, the acquisition of 2D NMR spectra allows a better separation between overlapped resonances while yielding accurate quantitative data when appropriate analytical protocols are implemented. Moreover, the experiment duration can be considerably reduced by applying fast acquisition methods. Here, we describe the general workflow to acquire fast quantitative 2D NMR spectra in the "omics" context. It is illustrated on three representative and complementary experiments: UF COSY, ZF‐TOCSY with nonuniform sampling, and HSQC with nonuniform sampling. After giving some details and recommendations on how to apply this protocol, its implementation in the case of targeted and untargeted metabolomics/lipidomics studies is described. [ABSTRACT FROM AUTHOR]

Homonuclear 13C-13C couplings at natural abundance can be measured using the J-modulated Adequate DoublE QUAntumTransfer Experiment (ADEQUATE) experiment. To somewhat ameliorate F1 digitization requirements, a scaling factor was incorporated into the original pulse sequence. Non-uniform sampling provides an obvious avenue to further facilitate the acquisition of 1 JCC and n JCC homonuclear coupling constant data. We introduce homonuclear decoupling (HD) analogous to that described for the 1,1-HD-ADEQUATE and 1,n-HD-ADEQUATE experiments and evaluate the combination of non-uniform sampling and HD on the acquisition of both 1 JCC and n JCC homonuclear 13C-13C coupling constants using ibuprofen as a model compound. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The concept of multidimensional spectroscopy, whose fiftieth birthday is approaching, has given the "tree" of chemical NMR the energy to grow, bloom, and bear fruit in the form of hundreds of new applications. Numerous alternative sampling methods have been available for more than three decades and have become widely accessible in standard NMR software packages for over 10 years. This special issue gathers papers on the applications of various alternative sampling methods in branches of NMR that are not yet fully conquered by NUS. [Extracted from the article]