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Practical Applications of NMR to Solve Real-World Problems

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 38810

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Dr. Robert Brinson

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Institute for Bioscience and Biotechnology Research, National Institute of Standards and Technology and the University of Maryland, 9600 Gudelsky Drive, Rockville, MD 20850, USA
Interests: biologics; proteins; nucleic acids; NMR; higher-order structure; chemometrics; method harmonization

Special Issue Information

Dear Colleagues,

Once primarily within the purview of academia, nuclear magnetic resonance spectroscopy (NMR) is now routinely used in many industry sectors, government agencies, and other applied research activities with great benefit. Such areas include agriculture, metabolomics, and complex mixtures, manufacturing and process monitoring, pharmaceuticals (biologics and small molecules), national security, forensics, energy, and renewables. Many similar technical challenges, and often regulatory burdens, are shared across these fields, yet there is often little cross-talk between the various NMR practitioners in each of these focused areas. Greater sharing of experience and expertise amongst practitioners of applied NMR would be of benefit to all.

With this in mind, this Special Issue will collect original papers and review articles across the broad array of current NMR applications in solving practical problems, with the goal of enabling cross-talk between academic, industrial, and government scientists. Emphasis will be placed on papers that address practical applications, including more basic research-oriented articles that seek to translate NMR methods into a new or different sector.

Dr. Robert Brinson
Guest Editor

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Keywords

NMR
Pharmaceuticals
Forensics
Agriculture
National security
Food science
Metabolomics
Energy and renewables
Process and reaction monitoring
Technology translation

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Published Papers (11 papers)

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Editorial

Jump to: Research

3 pages, 180 KiB

Open AccessEditorial

Practical Applications of NMR to Solve Real-World Problems

by Robert G. Brinson

Molecules 2021, 26(23), 7091; https://doi.org/10.3390/molecules26237091 - 24 Nov 2021

Cited by 3 | Viewed by 2421

Abstract

Nuclear magnetic resonance spectroscopy (NMR) is known to be a powerful technique for the characterization of small molecules and structural and dynamics studies of biomolecules [...] Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

Research

Jump to: Editorial

18 pages, 6509 KiB

Open AccessArticle

Study on Nuclear Magnetic Resonance Logging T₂ Spectrum Shape Correction of Sandstone Reservoirs in Oil-Based Mud Wells

by Jianmeng Sun, Jun Cai, Ping Feng, Fujing Sun, Jun Li, Jing Lu and Weichao Yan

Molecules 2021, 26(19), 6082; https://doi.org/10.3390/molecules26196082 - 8 Oct 2021

Cited by 8 | Viewed by 2758

Abstract

The oil-based mud filtrate will invade the formation under the overbalanced pressure during drilling operations. As a result, alterations will occur to the nuclear magnetic resonance (NMR) response characteristics of the original formation, causing the relaxation time of the NMR T₂ spectrum of the free fluid part to move towards a slower relaxation time. Consequently, the subsequent interpretation and petrophysical evaluation will be heavily impacted. Therefore, the actual measured T₂ spectrum needs to be corrected for invasion. For this reason, considering the low-porosity and low-permeability of sandstone gas formations in the East China Sea as the research object, a new method to correct the incorrect shape of the NMR logging T₂ spectrum was proposed in three main steps. First, the differences in the morphology of the NMR logging T₂ spectrum between oil-based mud wells and water-based mud wells in adjacent wells were analyzed based on the NMR relaxation mechanism. Second, rocks were divided into four categories according to the pore structure, and the NMR logging T₂ spectrum was extracted using the multidimensional matrix method to establish the T₂ spectrum of water-based mud wells and oil-based mud wells. Finally, the correctness of the method was verified by two T₂ spectrum correction examples of oil-based mud wells in the study area. The results show that the corrected NMR T₂ spectrum eliminates the influence of oil-based mud filtrate and improves the accuracy of NMR logging for calculating permeability. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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15 pages, 867 KiB

Open AccessArticle

¹H NMR Study of the HCa₂Nb₃O₁₀ Photocatalyst with Different Hydration Levels

by Marina G. Shelyapina, Oleg I. Silyukov, Elizaveta A. Andronova, Denis Y. Nefedov, Anastasiia O. Antonenko, Alexander Missyul, Sergei A. Kurnosenko and Irina A. Zvereva

Molecules 2021, 26(19), 5943; https://doi.org/10.3390/molecules26195943 - 30 Sep 2021

Cited by 11 | Viewed by 2068

Abstract

The photocatalytic activity of layered perovskite-like oxides in water splitting reaction is dependent on the hydration level and species located in the interlayer slab: simple or complex cations as well as hydrogen-bonded or non-hydrogen-bonded H₂O. To study proton localization and dynamics in the HCa₂Nb₃O₁₀·yH₂O photocatalyst with different hydration levels (hydrated—α-form, dehydrated—γ-form, and intermediate—β-form), complementary Nuclear Magnetic Resonance (NMR) techniques were applied. ¹H Magic Angle Spinning NMR evidences the presence of different proton containing species in the interlayer slab depending on the hydration level. For α-form, HCa₂Nb₃O₁₀·1.6H₂O, ¹H MAS NMR spectra reveal H₃O⁺. Its molecular motion parameters were determined from ¹H spin-lattice relaxation time in the rotating frame (T_1ρ) using the Kohlrausch-Williams-Watts (KWW) correlation function with stretching exponent β = 0.28:

E_{a} = 0.210 (2)

eV,

τ_{0} = 9.0 (1) \times 10^{- 12}

s. For the β-form, HCa₂Nb₃O₁₀·0.8H₂O, the only ¹H NMR line is the result of an exchange between lattice and non-hydrogen-bonded water protons. T_1ρ(1/T) indicates the presence of two characteristic points (224 and 176 K), at which proton dynamics change. The γ-form, HCa₂Nb₃O₁₀·0.1H₂O, contains bulk water and interlayer H⁺ in regular sites. ¹H NMR spectra suggest two inequivalent cation positions. The parameters of the proton motion, found within the KWW model, are as follows:

E_{a} = 0.217 (8)

eV,

τ_{0} = 8.2 (9) \times 10^{- 10}

s. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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16 pages, 2961 KiB

Open AccessArticle

Gadolinium-Based Paramagnetic Relaxation Enhancement Agent Enhances Sensitivity for NUS Multidimensional NMR-Based Metabolomics

by Chandrashekhar Honrao, Nathalie Teissier, Bo Zhang, Robert Powers and Elizabeth M. O’Day

Molecules 2021, 26(17), 5115; https://doi.org/10.3390/molecules26175115 - 24 Aug 2021

Cited by 6 | Viewed by 2827

Abstract

Gadolinium is a paramagnetic relaxation enhancement (PRE) agent that accelerates the relaxation of metabolite nuclei. In this study, we noted the ability of gadolinium to improve the sensitivity of two-dimensional, non-uniform sampled NMR spectral data collected from metabolomics samples. In time-equivalent experiments, the addition of gadolinium increased the mean signal intensity measurement and the signal-to-noise ratio for metabolite resonances in both standard and plasma samples. Gadolinium led to highly linear intensity measurements that correlated with metabolite concentrations. In the presence of gadolinium, we were able to detect a broad array of metabolites with a lower limit of detection and quantification in the low micromolar range. We also observed an increase in the repeatability of intensity measurements upon the addition of gadolinium. The results of this study suggest that the addition of a gadolinium-based PRE agent to metabolite samples can improve NMR-based metabolomics. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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11 pages, 2040 KiB

Open AccessArticle

Glycosylation States on Intact Proteins Determined by NMR Spectroscopy

by Audra A. Hargett, Aaron M. Marcella, Huifeng Yu, Chao Li, Jared Orwenyo, Marcos D. Battistel, Lai-Xi Wang and Darón I. Freedberg

Molecules 2021, 26(14), 4308; https://doi.org/10.3390/molecules26144308 - 16 Jul 2021

Cited by 8 | Viewed by 2900

Abstract

Protein glycosylation is important in many organisms for proper protein folding, signaling, cell adhesion, protein-protein interactions, and immune responses. Thus, effectively determining the extent of glycosylation in glycoprotein therapeutics is crucial. Up to now, characterizing protein glycosylation has been carried out mostly by liquid chromatography mass spectrometry (LC-MS), which requires careful sample processing, e.g., glycan removal or protein digestion and glycopeptide enrichment. Herein, we introduce an NMR-based method to better characterize intact glycoproteins in natural abundance. This non-destructive method relies on exploiting differences in nuclear relaxation to suppress the NMR signals of the protein while maintaining glycan signals. Using RNase B Man5 and RNase B Man9, we establish reference spectra that can be used to determine the different glycoforms present in heterogeneously glycosylated commercial RNase B. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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17 pages, 12306 KiB

Open AccessArticle

NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

by Deyun Wang, You Zhuo, Mike Karfunkle, Sharadrao M. Patil, Cameron J. Smith, David A. Keire and Kang Chen

Molecules 2021, 26(14), 4251; https://doi.org/10.3390/molecules26144251 - 13 Jul 2021

Cited by 11 | Viewed by 6793

Abstract

Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D ¹H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (D_M) of 3.3. The 2D ¹H-¹³C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for ¹H, 15 ppb for ¹³C and 98% peaks with equivalent peak height. Finally, 2D ¹H-¹⁵N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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19 pages, 3813 KiB

Open AccessArticle

Personalized Metabolic Profile by Synergic Use of NMR and HRMS

by Greta Petrella, Camilla Montesano, Sara Lentini, Giorgia Ciufolini, Domitilla Vanni, Roberto Speziale, Andrea Salonia, Francesco Montorsi, Vincenzo Summa, Riccardo Vago, Laura Orsatti, Edith Monteagudo and Daniel Oscar Cicero

Molecules 2021, 26(14), 4167; https://doi.org/10.3390/molecules26144167 - 8 Jul 2021

Cited by 5 | Viewed by 2866

Abstract

A new strategy that takes advantage of the synergism between NMR and UHPLC–HRMS yields accurate concentrations of a high number of compounds in biofluids to delineate a personalized metabolic profile (SYNHMET). Metabolite identification and quantification by this method result in a higher accuracy compared to the use of the two techniques separately, even in urine, one of the most challenging biofluids to characterize due to its complexity and variability. We quantified a total of 165 metabolites in the urine of healthy subjects, patients with chronic cystitis, and patients with bladder cancer, with a minimum number of missing values. This result was achieved without the use of analytical standards and calibration curves. A patient’s personalized profile can be mapped out from the final dataset’s concentrations by comparing them with known normal ranges. This detailed picture has potential applications in clinical practice to monitor a patient’s health status and disease progression. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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12 pages, 1801 KiB

Open AccessArticle

Screening Metal–Organic Frameworks for Separation of Binary Solvent Mixtures by Compact NMR Relaxometry

by Marc Wagemann, Natalia Radzik, Artur Krzyżak and Alina Adams

Molecules 2021, 26(12), 3481; https://doi.org/10.3390/molecules26123481 - 8 Jun 2021

Cited by 3 | Viewed by 2290

Abstract

Metal–organic frameworks (MOFs) have great potential as an efficient alternative to current separation and purification procedures of a large variety of solvent mixtures—a critical process in many applications. Due to the huge number of existing MOFs, it is of key importance to identify high-throughput analytical tools, which can be used for their screening and performance ranking. In this context, the present work introduces a simple, fast, and inexpensive approach by compact low-field proton nuclear magnetic resonance (NMR) relaxometry to investigate the efficiency of MOF materials for the separation of a binary solvent mixture. The mass proportions of two solvents within a particular solvent mixture can be quantified before and after separation with the help of a priori established correlation curves relating the effective transverse relaxation times T_2eff and the mass proportions of the two solvents. The new method is applied to test the separation efficiency of powdered UiO-66(Zr) for various solvent mixtures, including linear and cyclic alkanes and benzene derivate, under static conditions at room temperature. Its reliability is demonstrated by comparison with results from ¹H liquid-state NMR spectroscopy. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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16 pages, 38864 KiB

Open AccessArticle

Multiphase Flow Regime Characterization and Liquid Flow Measurement Using Low-Field Magnetic Resonance Imaging

by Rutger R. Tromp and Lucas M. C. Cerioni

Molecules 2021, 26(11), 3349; https://doi.org/10.3390/molecules26113349 - 2 Jun 2021

Cited by 8 | Viewed by 3442

Abstract

Multiphase flow metering with operationally robust, low-cost real-time systems that provide accuracy across a broad range of produced volumes and fluid properties, is a requirement across a range of process industries, particularly those concerning petroleum. Especially the wide variety of multiphase flow profiles that can be encountered in the field provides challenges in terms of metering accuracy. Recently, low-field magnetic resonance (MR) measurement technology has been introduced as a feasible solution for the petroleum industry. In this work, we study two phase air-water horizontal flows using MR technology. We show that low-field MR technology applied to multiphase flow has the capability to measure the instantaneous liquid holdup and liquid flow velocity using a constant gradient low flip angle CPMG (LFA-CPMG) pulse sequence. LFA-CPMG allows representative sampling of the correlations between liquid holdup and liquid flow velocity, which allows multiphase flow profiles to be characterized. Flow measurements based on this method allow liquid flow rate determination with an accuracy that is independent of the multiphase flow profile observed in horizontal pipe flow for a wide dynamic range in terms of the average gas and liquid flow rates. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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14 pages, 1056 KiB

Open AccessArticle

Establishing a Metabolite Extraction Method to Study the Metabolome of Blastocystis Using NMR

by Jamie M. Newton, Emma L. Betts, Lyto Yiangou, Jose Ortega Roldan, Anastasios D. Tsaousis and Gary S. Thompson

Molecules 2021, 26(11), 3285; https://doi.org/10.3390/molecules26113285 - 29 May 2021

Cited by 5 | Viewed by 3695

Abstract

Blastocystis is an opportunistic parasite commonly found in the intestines of humans and other animals. Despite its high prevalence, knowledge regarding Blastocystis biology within and outside the host is limited. Analysis of the metabolites produced by this anaerobe could provide insights that can help map its metabolism and determine its role in both health and disease. Due to its controversial pathogenicity, these metabolites could define its deterministic role in microbiome’s “health” and/or subsequently resolve Blastocystis’ potential impact in gastrointestinal health. A common method for elucidating the presence of these metabolites is through ¹H nuclear magnetic resonance (NMR). However, there are currently no described benchmarked methods available to extract metabolites from Blastocystis for ¹H NMR analysis. Herein, several extraction solvents, lysis methods and incubation temperatures were compared for their usefulness as an extraction protocol for this protozoan. Following extraction, the samples were freeze-dried, re-solubilized and analysed with ¹H NMR. The results demonstrate that carrying out the procedure at room temperature using methanol as an extraction solvent and bead bashing as a lysis technique provides a consistent, reproducible and efficient method to extract metabolites from Blastocystis for NMR. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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7 pages, 15119 KiB

Open AccessArticle

Use of the 2D ¹H-¹³C HSQC NMR Methyl Region to Evaluate the Higher Order Structural Integrity of Biopharmaceuticals

by Tsang-Lin Hwang, Dipanwita Batabyal, Nicholas Knutson and Mats Wikström

Molecules 2021, 26(9), 2714; https://doi.org/10.3390/molecules26092714 - 5 May 2021

Cited by 9 | Viewed by 4806

Abstract

The higher-order structure (HOS) of protein therapeutics is directly related to the function and represents a critical quality attribute. Currently, the HOS of protein therapeutics is characterized by methods with low to medium structural resolution, such as Fourier transform infrared (FTIR), circular dichroism (CD), intrinsic fluorescence spectroscopy (FLD), and differential scanning calorimetry (DSC). High-resolution nuclear magnetic resonance (NMR) methods have now been introduced, representing powerful approaches for HOS characterization (HOS by NMR). NMR is a multi-attribute method with unique abilities to give information on all structural levels of proteins in solution. In this study, we have compared 2D ¹H-¹³C HSQC NMR with two established biophysical methods, i.e., near-ultraviolet circular dichroism (NUV-CD) and intrinsic fluorescence spectroscopy, for the HOS assessments for the folded and unfolded states of two monoclonal antibodies belonging to the subclasses IgG1 and IgG2. The study shows that the methyl region of the ¹H-¹³C HSQC NMR spectrum is sensitive to both the secondary and tertiary structure of proteins and therefore represents a powerful tool in assessing the overall higher-order structural integrity of biopharmaceutical molecules. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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