Journal of Magnetic Resonance Open最新文献

Inhibition of the exonuclease activity of Three-prime Repair EXonuclease 1 (TREX1) has emerged as a potential novel immunotherapeutic strategy. Herein we describe our screening approach to find initial low-affinity fragment hits for TREX1 from our ¹⁹F library and the use of both ligand- and target-based NMR methods for hit confirmation and validation. In a further step to support the early hit expansion stage we describe our setup of a ¹⁹F competition assay for K_I determination of analogs.

In this mini-review, we examine the exactness of the available theoretical methods for describing the effects of a radio frequency (RF) pulse on a spin I=1/2 system. Employing an isolated spin as a model system, the interplay between the internal (anisotropic) interactions and the external parameters (such as sample spinning frequency, amplitude of the pulse etc.) is discussed through comparison between simulations emerging from analytic and numerical methods. Accordingly, the suitability of the analytic methods are examined and classified into regimes based on the magnitudes of the internal and external parameters.

The tri-phosphate and sodium ion environments in well crystallized disodium 5′adenosine triphosphate trihydrate (ATP•3H₂O) are investigated using high-resolution solid-state NMR spectroscopy and ab initio calculations. The six inequivalent phosphorus sites resolved in ³¹P MAS spectra have been assigned on the basis of experimentally obtained results and theoretical ab initio quantum chemical calculations of ³¹P chemical shielding tensors with increased numerical accuracy. Aided by ³¹P-³¹P dipolar connectivity established in DQ-SQ correlation experiment and DFT calculations carried out at the B3LYP/(aug-cc-pDVZ(3s,2p,1d), 6–31G(d,p)) level, phosphorus resonance assignments in MAS spectra have been made and the ³¹P chemical shielding anisotropies and tensor orientations in the molecule-fixed frame have been determined. ³¹P shielding tensors are found to be oriented with the most shielded direction nearly perpendicular to the O-P-O plane involving the two adjoining oxygens. The complete resolution of the four sodium sites has been achieved from 3Q-MAS experiments performed at 7.05 T and this has enabled ²³Na quadrupole parameters to be determined experimentally and compared with theoretical calculations. Besides aiding a partial resonance assignment of the ²³Na 3Q-MAS spectrum, our HF/6–311++G(2d,2p) calculations of ²³Na EFG tensors show that for two sodium sites which are tightly coordinated the orientation of the EFG tensor is distinct. These exhibit unique directions along which the field gradient is the smallest and largest.

Advances in liquid state hyperpolarization methods have enabled new applications of high-resolution NMR spectroscopy. Utilizing strong signal enhancements from hyperpolarization allows performing NMR spectroscopy at low concentration, or with high time resolution. Making use of the high, but rapidly decaying hyperpolarization in the liquid state requires new techniques to interface hyperpolarization equipment with liquid state NMR spectrometers. This article highlights rapid injection, high resolution NMR spectroscopy with hyperpolarization produced by the techniques of dissolution dynamic nuclear polarization (D-DNP) and para-hydrogen induced polarization (PHIP). These are popular, albeit not the only methods to produce high polarization levels for liquid samples. Gas and liquid driven sample injection techniques are compatible with both of these hyperpolarization methods. The rapid sample injection techniques are combined with adapted NMR experiments working in a single, or small number of scans. They expand the application of liquid state hyperpolarization to spins with comparably short relaxation times, provide enhanced control over sample conditions, and allow for mixing experiments to study reactions in real time.

Measurement of distances from dipolar couplings is essential for structural characterization, refinement and validation using the solid-state nuclear magnetic resonance (ssNMR) spectroscopy. Particularly, knowledge about NH dipolar interactions in biological solids is important for understanding the hydrogen (H)-bonding interactions, molecular geometry and spin dynamics. In this regard, we have proposed a proton-detected two-dimensional (2D) ¹⁵N-¹H dipolar coupling/¹H chemical shift correlation experiment using the C-symmetry based windowless recoupling of chemical shift anisotropy (ROCSA) in combination with the DIPSHIFT pulse-based method for the measurement of short NH distances in the isotopically labeled and naturally abundant biological solids at fast magic angle spinning (MAS) rates (40–70 kHz). Our proposed method results in undistorted recoupled ¹⁵N-¹H dipolar coupling powder lineshapes that are free from the recoupled ¹H CSA contributions under the ¹⁵N evolution, a feature that is essential for the measurement of NH distances with improved accuracy (± 500 Hz in terms of the NH dipolar couplings). The pulse sequence developed in the present study is also insensitive to the ¹H–¹H homonuclear dipolar interactions, relaxation effects owing to its constant-time implementation, and t₁-noise from the fluctuations in the MAS.

Zero-to-ultra-low-field nuclear magnetic resonance (ZULF NMR) is fast emerging as a viable spectroscopic approach to study samples under conditions dominated by internal spin interactions. In the absence of the truncating effects of Zeeman interaction, the NMR signal is determined by $J$-coupling, dipole-dipole, and/or quadrupolar interactions. But, the low spin-precession frequencies and equilibrium spin polarisation in low external fields necessitate the use of special techniques for detecting the signals. In this article, spin evolution in ultra-low-field regime for various systems is studied and the expected NMR signals are evaluated for solid samples. The methodologies that can be used to make low-field detection feasible especially in case of solid samples are described.

Rod-like mesogens with the rigid core constituted by a combination of phenyl and thiophene moieties reveal interesting orientational ordering behavior. In this article, four rod-like mesogens constructed with a terminal alkoxy chain on only one side of the mesogenic core with the other end terminated with either a phenyl or thiophene ring have been investigated using ¹³C NMR spectroscopy. The mesogen with the terphenyl moiety in the core exhibited polymesomorphism with nematic, smectic C, and smectic I mesophases with very high clearing temperatures. The replacement of terphenyl with terthiophene moiety resulted in suppression of polymesomorphism, with only nematic mesophase being observed. Mesogens with single terminal thiophene connected to two phenyl rings in the core also showed only the nematic mesophase for both the possibilities of linking the core to the thiophene ring at the 2- and 3- positions. One- and two- dimensional ¹³C NMR spectra have been obtained in the mesophases from which the alignment induced chemical shifts of the ring carbons and ¹³C-¹H dipolar couplings, as well as the local order parameters, have been obtained. The considerable difference in ¹³C chemical shifts and the ¹³C-¹H dipolar couplings of thiophene ring with change in position of the linking unit is attributed to the difference in the order parameters of the thiophene moiety between the two cases. The data obtained on the ordering of phenyl and thiophene rings in the core units offered information into the effect of replacing the phenyl ring with the thiophene ring. So also, the change of position of the link to the thiophene moiety provided important insights into the orientational behavior in the liquid crystalline phase and on the molecular structure.

Satellite transition selective excitation/inversion of abundant spins across chemical shifts offers a robust opportunity for sensitivity enhancement of rare spins that are coupled to them. It is also well established that reconversion of rare spin double quantum coherence (DQC) to single quantum-single transitions (SQ-ST's) over a wide range of chemical shifts offers sensitivity enhancement in INADEQUATE-style experiments. The present contribution gives an overview of the latter category of experiments, including a brief summary of the literature, and the contributions from our Lab. In particular, the transition selective “composite refocusing” approach of Sørensen and his group is discussed for reconversion of DQC to SQ-ST's. A shorter transition selective DQC reconversion module introduced from our Lab is also described. A 2D rare spin correlation experiment introduced by us is then reviewed, in which we replace rare spin DQ evolution with immediate reconversion of DQC to SQ-ST's, followed by evolution of SQ-ST's, that is then terminated by a mixing period to deliver a diagonal-free COSY-like correlation map. Finally, our ‘indirect’, ¹H detected version of this experiment is reviewed. Transition selective reconversion in ADEQUATE-style experiments was also introduced by us and is briefly mentioned. Interestingly, partial ¹H transition selectivity is shown to result as a consequence of reconversion of rare spin DQC to SQ-ST's, followed by coherence order selective heteronuclear reverse transfer. The performance of these experiments when applied to small molecules is illustrated.

Reorientational dynamics—motion defined by changes in the direction of a vector or tensor—determine relaxation behavior in nuclear magnetic resonance (NMR). However, if multiple processes exist that result in reorientation, then analyzing the net effects becomes a complex task, so that one ideally would separate those motions to simplify analysis. The model-free and two-step approaches have established the separability of the total correlation function of reorientation motion into contributions from statistically independent motions. Separability has been used to justify the analysis of experimental relaxation rate constants by fitting data to a total correlation function resulting from the product of two or three individual correlation functions, each representing an independent motion. The resulting parameters are used to describe motion in the molecule, but if multiple internal motions are present, interpreting those parameters is not trivial. We suggest an alternative approach: quantitative and timescale-specific comparison of experiment and simulation, as previously established using the detector analysis. This is followed by separation of simulated correlation functions into independent motions, and timescale-specific parameterization of the results, such that one may determine how each motion contributes to experimental parameters. We establish protocols for the separation of the correlation function into components using coordinates from molecular dynamics simulation. Separation is achieved by defining a series of frames, where the frames iteratively split the total motion into contributions from motion within each frame and of each frame. Then timescale specific parameters (e.g. detector responses) describing the total motion may be interpreted in terms of the timescale-specific parameterization of the individual motions.