Monday, June 29, 2015

Magic Angle Spinning NMR Spectroscopy: A Versatile Technique for Structural and Dynamic Analysis of Solid-Phase Systems

This review gives a comprehensive overview of the state-of-the-art of magic-angle spinning (MAS), solid-state NMR spectroscopy, including DNP-NMR spectroscopy.


1. Polenova, T., R. Gupta, and A. Goldbourt, Magic angle spinning NMR spectroscopy: a versatile technique for structural and dynamic analysis of solid-phase systems. Anal Chem, 2015. 87(11): p. 5458-69.


Magic Angle Spinning (MAS) NMR spectroscopy is a powerful method for analysis of a broad range of systems, including inorganic materials, pharmaceuticals, and biomacromolecules. The recent developments in MAS NMR instrumentation and methodologies opened new vistas to atomic-level characterization of a plethora of chemical environments previously inaccessible to analysis, with unprecedented sensitivity and resolution. 

Friday, June 26, 2015

Up to 100% Improvement in Dynamic Nuclear Polarization Solid-State NMR Sensitivity Enhancement of Polymers by Removing Oxygen


Le, D., et al., Up to 100% Improvement in Dynamic Nuclear Polarization Solid-State NMR Sensitivity Enhancement of Polymers by Removing Oxygen. Macromol Rapid Commun, 2015: p. n/a-n/a.


High-field dynamic nuclear polarization (DNP) has emerged as a powerful technique for improving the sensitivity of solid-state NMR (SSNMR), yielding significant sensitivity enhancements for a variety of samples, including polymers. Overall, depending upon the type of polymer, the molecular weight, and the DNP sample preparation method, sensitivity enhancements between 5 and 40 have been reported. These promising enhancements remain, however, far from the theoretical maximum (>1000). Crucial to the success of DNP SSNMR is the DNP signal enhancement (epsilonDNP ), which is the ratio of the NMR signal intensities with and without DNP. It is shown here that, for polymers exhibiting high affinity toward molecular oxygen (e.g., polystyrene), removing part of the absorbed (paramagnetic) oxygen from the solid-state samples available as powders (instead of dissolved or dispersed in a solvent) increases proton nuclear relaxation times and epsilonDNP , hereby providing up to a two-fold sensitivity increase (i.e., a four-fold reduction in experimental time).

[NMR] June 30th: deadline registration Hyperpolarized Magnetic Resonance Meeting, Egmond aan Zee, the Netherlands

From the Ampere Magnetic Resonance List



You that you only have a few days left for submitting abstracts for poster presentations during the Hyperpolarized Magnetic Resonance meeting! The deadline for registrations is also on June 30th!

This symposium combines the COST action EUROHyperPOL final meeting with the 5th international DNP symposium.

Where: Egmond aan Zee (the Netherlands)
When: Augustus 31 - September 4, 2015

Deadlines
Registration 30/06/2015
Abstract submission
(poster-presentations only) 30/06/2015


With kind regards,

Marc Baldus, Arno Kentgens, Jan van Bentum, Klaartje Houben, Barbara Hendricx, Marian de With (organizing committee)

-- 
Marian de With
Radboud University | Institute for Molecules and Materials
Secretary for depts. of Biophysical Chemistry, Solid State NMR and Theoretical Chemistry
Tel. +31 24 3652678 

Visiting address:
Heyendaalseweg 135 | 6525 AJ Nijmegen | HG03.344
Postal address:
Postbox 9010 | Internal postbus 84 | 6500 GL Nijmegen 

Out of office on Mondays!

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Wednesday, June 24, 2015

Improved Stability and Spectral Quality in Ex Situ Dissolution DNP Using an Improved Transfer Device


Katsikis, S., et al., Improved Stability and Spectral Quality in Ex Situ Dissolution DNP Using an Improved Transfer Device. Appl. Magn. Reson., 2015: p. 1-7.


Dissolution dynamic nuclear polarization (DNP) has become one of the predominant implementations for DNP. However, the technical implementation of transferring the sample from the polarizer to the nuclear magnetic resonance (NMR) system remains challenging. There is a need for additional technical optimizations in order to use dissolution DNP for biochemical and chemical applications. Here we show how a newly designed pressure dissolution kit considerably improves spectral quality and stability by enabling highly reliable and fast sample transfer to the NMR system.

[NMR] PhD position / Utrecht / solid-state NMR / membrane proteins

From the Ampere Magnetic Resonance List


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PhD position / Utrecht / solid-state NMR / membrane proteins

We invite applications for a 4-years PhD position in the newly founded subgroup of Dr. Markus Weingarth at the Bijvoet Center, Utrecht University, The Netherlands. The research is embedded in the NMR group of Prof. Marc Baldus.

The research will focus on supramolecular interactions of membrane proteins using a combined approach of modern solid-state NMR methods & modern MD simulations methods.

We offer access to high-field NMR machines (950, 800, 700, 500, 400 MHz magnets for solid-state NMR / 900 MHz magnet for solution NMR). A 1.2 GHz machine will be installed within the next years.

The 950, 800 and 700 MHz machines are equipped with fast-spinning 1.3 mm probes. The 800 and 400 MHz magnets are equipped for DNP.

The candidate will have access to a powerful computational infrastructure and a well-equipped protein expression lab with a strong expertise in membrane proteins.

We participate in the COST action CM1306 ‘Understanding Movement and Mechanism in Molecular Machines’, a European network that fosters collaboration and exchange among >40 research groups, from which the candidate can benefit.

Applicants should have a degree in biochemistry/molecular biology/biophysics or a related discipline. Cross-disciplinary applications are welcome. Experience in molecular / cell biology techniques / protein expression is strongly desirable. Experience in MD simulations, NMR (liquids or solids) or programming is a plus, but not required.

The candidate is offered a full-time position for 4 years. The salary is supplemented with a holiday bonus of 8.0% and an end-of-year bonus of 8,3% per year. In addition we offer a pension scheme, partially paid parental leave and flexible employment conditions. Conditions are based on the Collective Labour Agreement Dutch Universities. The research group will provide the candidate with necessary support on all aspects of the project. The salary starts at € 2.042.- and increases to € 2.612.- gross per month in the fourth year. The starting date is September 2015 or later. The PhD position is founded by a VIDI grant of the “Netherlands Organisation for Scientific Research” (NWO) to Dr. Weingarth.

Please send CV & application documents including the names/addresses of two references to:

Dr. Markus Weingarth
Phone: +31 30 253 2875

See here for further information (or ask by email):

See also here for selection of recent project-related works:

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Monday, June 22, 2015

Improving the hyperpolarization of (31)P nuclei by synthetic design


Burns, M.J., et al., Improving the hyperpolarization of (31)P nuclei by synthetic design. J Phys Chem B, 2015. 119(15): p. 5020-7.


Traditional (31)P NMR or MRI measurements suffer from low sensitivity relative to (1)H detection and consequently require longer scan times. We show here that hyperpolarization of (31)P nuclei through reversible interactions with parahydrogen can deliver substantial signal enhancements in a range of regioisomeric phosphonate esters containing a heteroaromatic motif which were synthesized in order to identify the optimum molecular scaffold for polarization transfer. A 3588-fold (31)P signal enhancement (2.34% polarization) was returned for a partially deuterated pyridyl substituted phosphonate ester. This hyperpolarization level is sufficient to allow single scan (31)P MR images of a phantom to be recorded at a 9.4 T observation field in seconds that have signal-to-noise ratios of up to 94.4 when the analyte concentration is 10 mM. In contrast, a 12 h 2048 scan measurement under standard conditions yields a signal-to-noise ratio of just 11.4. (31)P-hyperpolarized images are also reported from a 7 T preclinical scanner.

Friday, June 19, 2015

Development of the Multifrequency Gyrotron FU CW GV with Gaussian Beam Output


Tatematsu, Y., et al., Development of the Multifrequency Gyrotron FU CW GV with Gaussian Beam Output. J Infrared Milli Terahz Waves, 2015: p. 1-12.


Gyrotron FU CW GV has been developed as a multifrequency gyrotron for operation over the frequency range from 162 to 265 GHz at frequencies separated by steps of approximately 10 GHz. The oscillation modes were selected; the radii of the caustic surfaces for the electromagnetic waves of the modes had similar values in the waveguide, and it was therefore expected that these modes would be converted into Gaussian beams by a mode converter. In reality, more than ten modes oscillated and the Gaussian-like beams were radiated. A double-disk window with variable spacing maintains the transmittance through the window at a high level over a wide range of frequencies. Using this window, output powers of more than 1 kW were observed for almost all the expected modes.

Wednesday, June 17, 2015

Dynamic nuclear polarization of membrane proteins: covalently bound spin-labels at protein-protein interfaces


Wylie, B.J., et al., Dynamic nuclear polarization of membrane proteins: covalently bound spin-labels at protein-protein interfaces. J Biomol NMR, 2015. 61(3-4): p. 361-7.


We demonstrate that dynamic nuclear polarization of membrane proteins in lipid bilayers may be achieved using a novel polarizing agent: pairs of spin labels covalently bound to a protein of interest interacting at an intermolecular interaction surface. For gramicidin A, nitroxide tags attached to the N-terminal intermolecular interface region become proximal only when bimolecular channels forms in the membrane. We obtained signal enhancements of sixfold for the dimeric protein. The enhancement effect was comparable to that of a doubly tagged sample of gramicidin C, with intramolecular spin pairs. This approach could be a powerful and selective means for signal enhancement in membrane proteins, and for recognizing intermolecular interfaces.

Monday, June 15, 2015

Imaging metabolism with hyperpolarized (13)c-labeled cell substrates


Brindle, K.M., Imaging metabolism with hyperpolarized (13)c-labeled cell substrates. J Am Chem Soc, 2015. 137(20): p. 6418-27.


Non-invasive (13)C magnetic resonance spectroscopy measurements of the uptake and subsequent metabolism of (13)C-labeled substrates is a powerful method for studying metabolic fluxes in vivo. However, the technique has been hampered by a lack of sensitivity, which has limited both the spatial and temporal resolution. The introduction of dissolution dynamic nuclear polarization in 2003, which by radically enhancing the nuclear spin polarization of (13)C nuclei in solution can increase their sensitivity to detection by more than 10(4)-fold, revolutionized the study of metabolism using magnetic resonance, with temporal and spatial resolutions in the seconds and millimeter ranges, respectively. The principal limitation of the technique is the short half-life of the polarization, which at approximately 20-30 s in vivo limits studies to relatively fast metabolic reactions. Nevertheless, pre-clinical studies with a variety of different substrates have demonstrated the potential of the method to provide new insights into tissue metabolism and have paved the way for the first clinical trial of the technique in prostate cancer. The technique now stands on the threshold of more general clinical translation. I consider here what the clinical applications might be, which are the substrates that most likely will be used, how will we analyze the resulting kinetic data, and how we might further increase the levels of polarization and extend polarization lifetime.

Friday, June 12, 2015

Dynamic nuclear polarization in the hyperfine-field-dominant region


Lee, S.-J., et al., Dynamic nuclear polarization in the hyperfine-field-dominant region. J. Magn. Reson., 2015. 255(0): p. 114-121.


Dynamic nuclear polarization (DNP) allows measuring enhanced nuclear magnetic resonance (NMR) signals. Though the efficiency of DNP has been known to increase at low fields, the usefulness of DNP has not been throughly investigated yet. Here, using a superconducting quantum interference device-based NMR system, we performed a series of DNP experiments with a nitroxide radical and measured DNP spectra at several magnetic fields down to sub-microtesla. In the DNP spectra, the large overlap of two peaks having opposite signs results in net enhancement factors, which are significantly lower than theoretical expectations [30] and nearly invariant with respect to magnetic fields below the Earth’s field. The numerical analysis based on the radical’s Hamiltonian provides qualitative explanations of such features. The net enhancement factor reached 325 at maximum experimentally, but our analysis reveals that the local enhancement factor at the center of the rf coil is 575, which is unaffected by detection schemes. We conclude that DNP in the hyperfine-field-dominant region yields sufficiently enhanced NMR signals at magnetic fields above 1 μ T.

Wednesday, June 10, 2015

Cucurbit[6]uril is an ultrasensitive (129)Xe NMR contrast agent


Wang, Y. and I.J. Dmochowski, Cucurbit[6]uril is an ultrasensitive (129)Xe NMR contrast agent. Chem Commun (Camb), 2015. 51(43): p. 8982-5.


A lack of molecular contrast agents has slowed the application of ultrasensitive hyperpolarized (129)Xe NMR methods. Here, we report that commercially available cucurbit[6]uril (CB[6]) undergoes rapid xenon exchange kinetics at 300 K, and is detectable by Hyper-CEST NMR at 1.8 pM in PBS and at 1 muM in human plasma where many molecules, including polyamines, can compete with xenon for CB[6] binding.

Monday, June 8, 2015

Hyperpolarization of "Neat" Liquids by NMR Signal Amplification by Reversible Exchange


Shchepin, R.V., et al., Hyperpolarization of "Neat" Liquids by NMR Signal Amplification by Reversible Exchange. J Phys Chem Lett, 2015. 6(10): p. 1961-1967.


We report NMR Signal Amplification by Reversible Exchange (SABRE) hyperpolarization of the rare isotopes in "neat" liquids, each composed only of an otherwise pure target compound with isotopic natural abundance (n.a.) and millimolar concentrations of dissolved catalyst. Pyridine (Py) or Py derivatives are studied at 0.4% isotopic natural abundance 15N, deuterated, 15N enriched, and in various combinations using the SABRE-SHEATH variant (microTesla magnetic fields to permit direct 15N polarization from parahydrogen via reversible binding and exchange with an Ir catalyst). We find that the dilute n.a. 15N spin bath in Py still channels spin order from parahydrogen to dilute 15N spins, without polarization losses due to the presence of 14N or 2H. We demonstrate P 15N approximately 1% (a gain of 2900 fold relative to thermal polarization at 9.4 T) at high substrate concentrations. This fundamental finding has a significant practical benefit for screening potentially hyperpolarizable contrast agents without labeling. The capability of screening at n.a. level of 15N is demonstrated on examples of mono- and dimethyl-substituted Py (picolines and lutidines previously identified as promising pH sensors), showing that the presence of a methyl group in the ortho position significantly decreases SABRE hyperpolarization.

Friday, June 5, 2015

Hyperpolarized Water to Study Protein–Ligand Interactions


Chappuis, Q., et al., Hyperpolarized Water to Study Protein–Ligand Interactions. The Journal of Physical Chemistry Letters, 2015. 6(9): p. 1674-1678.


The affinity between a chosen target protein and small molecules is a key aspect of drug discovery. Screening by popular NMR methods such as Water-LOGSY suffers from low sensitivity and from false positives caused by aggregated or denatured proteins. This work demonstrates that the sensitivity of Water-LOGSY can be greatly boosted by injecting hyperpolarized water into solutions of proteins and ligands. Ligand binding can be detected in a few seconds, whereas about 30 min is usually required without hyperpolarization. Hyperpolarized water also enhances proton signals of proteins at concentrations below 20 ?M so that one can verify in a few seconds whether the proteins remain intact or have been denatured

Wednesday, June 3, 2015

Toward Quantitative Measurements of Enzyme Kinetics by Dissolution Dynamic Nuclear Polarization


Miclet E, Abergel D, Bornet A, Milani J, Jannin S, Bodenhausen G. Toward Quantitative Measurements of Enzyme Kinetics by Dissolution Dynamic Nuclear Polarization. The Journal of Physical Chemistry Letters. 2014;5(19):3290-5.


Dissolution dynamic nuclear polarization (D-DNP) experiments enabled us to study the kinetics of the enzymatic phosphorylation reaction of glucose to form glucose-6-phosphate (G6P) by hexokinase (HK), with or without the presence of an excess of G6P, which is known to be an inhibitor of the enzyme. Against all expectations, our observations demonstrate that the phosphorylation of both α and ? glucose anomers occurs with comparable kinetics. The catalytic constant of the reaction was estimated based on a simple kinetic model tailored for hyperpolarized systems.

Monday, June 1, 2015

A "Smart" (129)Xe NMR Biosensor for pH-Dependent Cell Labeling


Riggle BA, Wang Y, Dmochowski IJ. A "Smart" (129)Xe NMR Biosensor for pH-Dependent Cell Labeling. J Am Chem Soc. 2015;137(16):5542-8.


Here we present a "smart" xenon-129 NMR biosensor that undergoes a peptide conformational change and labels cells in acidic environments. To a cryptophane host molecule with high Xe affinity, we conjugated a 30mer EALA-repeat peptide that is alpha-helical at pH 5.5 and disordered at pH 7.5. The (129)Xe NMR chemical shift at room temperature was strongly pH-dependent (Deltadelta = 3.4 ppm): delta = 64.2 ppm at pH 7.5 vs delta = 67.6 ppm at pH 5.5, where Trp(peptide)-cryptophane interactions were evidenced by Trp fluorescence quenching. Using hyper-CEST NMR, we probed peptidocryptophane detection limits at low-picomolar (10(-11) M) concentration, which compares favorably to other NMR pH reporters at 10(-2)-10(-3) M. Finally, in biosensor-HeLa cell solutions, peptide-cell membrane insertion at pH 5.5 generated a 13.4 ppm downfield cryptophane-(129)Xe NMR chemical shift relative to pH 7.5 studies. This highlights new uses for (129)Xe as an ultrasensitive probe of peptide structure and function, along with potential applications for pH-dependent cell labeling in cancer diagnosis and treatment.