Abstract
High-resolution solid-state NMR (SSNMR) of paramagnetic systems has been largely unexplored because of various technical difficulties due to large hyperfine shifts, which have limited the success of previous studies through depressed sensitivity/resolution and lack of suitable assignment methods. Our group recently introduced an approach using "very fast" magic angle spinning (VFMAS) for SSNMR of paramagnetic systems, which opened an avenue toward routine analyses of small paramagnetic systems by (13)C and (1)H SSNMR [Y. Ishii et al., J. Am. Chem. Soc. 125, 3438 (2003); N. P. Wickramasinghe et al., ibid. 127, 5796 (2005)]. In this review, we discuss our recent progress in establishing this approach, which offers solutions to a series of problems associated with large hyperfine shifts. First, we demonstrate that MAS at a spinning speed of 20 kHz or higher greatly improves sensitivity and resolution in both (1)H and (13)C SSNMR for paramagnetic systems such as Cu(II)(DL-alanine)(2)H(2)O (Cu(DL-Ala)(2)) and Mn(acac)(3), for which the spectral dispersions due to (1)H hyperfine shifts reach 200 and 700 ppm, respectively. Then, we introduce polarization transfer methods from (1)H spins to (13)C spins with high-power cross polarization and dipolar insensitive nuclei enhanced by polarization transfer (INEPT) in order to attain further sensitivity enhancement and to correlate (1)H and (13)C spins in two-dimensional (2D) SSNMR for the paramagnetic systems. Comparison of (13)C VFMAS SSNMR spectra with (13)C solution NMR spectra revealed superior sensitivity in SSNMR for Cu(DL-Ala)(2), Cu(Gly)(2), and V(acac)(3). We discuss signal assignment methods using one-dimensional (1D) (13)C SSNMR (13)C-(1)H rotational echo double resonance (REDOR) and dipolar INEPT methods and 2D (13)C(1)H correlation SSNMR under VFMAS, which yield reliable assignments of (1)H and (13)C resonances for Cu(Ala-Thr). Based on the excellent sensitivity/resolution and signal assignments attained in the VFMAS approach, we discuss methods of elucidating multiple distance constraints in unlabeled paramagnetic systems by combing simple measurements of (13)C T(1) values and anisotropic hyperfine shifts. Comparison of experimental (13)C hyperfine shifts and ab initio calculated shifts for alpha- and beta-forms of Cu(8-quinolinol)(2) demonstrates that (13)C hyperfine shifts are parameters exceptionally sensitive to small structural difference between the two polymorphs. Finally, we discuss sensitivity enhancement with paramagnetic ion doping in (13)C SSNMR of nonparamagnetic proteins in microcrystals. Fast recycling with exceptionally short recycle delays matched to short (1)H T(1) of approximately 60 ms in the presence of Cu(II) doping accelerated 1D (13)C SSNMR for ubiquitin and lysozyme by a factor of 7.3-8.4 under fast MAS at a spinning speed of 40 kHz. It is likely that the VFMAS approach and use of paramagnetic interactions are applicable to a variety of paramagnetic systems and nonparamagnetic biomolecules.
Highlights
More than one-third of the elements in the Periodic Table exhibit paramagnetism
We recently demonstrated that further sensitivity enhancement in 13C SSNMR spectra for paramagnetic systems can be obtained using polarization transfer from 1H spins with the strong rf fields available in
We demonstrated the possibility of sensitivity enhancement by polarization transfer under VFMAS for samples possessing extremely large hyperfine shifts such as Mnacac3.25 Figure 3͑dshows a 1D 13C VFMAS spectrum of Mnacac3 obtained by a rapid repetition of the dipolar INEPT sequence1.5 ms/scanin a common experimental time witha–͑c10 min
Summary
Antitumor drugs, which are often administered as solid substances. Their morphologies and structures in solids substantially differentiate stability and bioavailability of these drugs. In contrast, development of novel paramagnetic complexes has been often hindered by lack of efficient characterization methods, in particular, for noncrystalline solids. Our group recently introduced a simple and effective approach for SSNMR of paramagnetic systems using fast MAS at a spinning speed of 20 kHz or more, which we call very-fast MASVFMASapproach.19,20 This approach has substantially simplified SSNMR spectroscopy of paramagnetic systems by eliminating strong anisotropic interactions such as 1H – 13C and 1H – 1H dipolar couplings and 1H and 13C pseudocontact shifts by VFMAS without rf pulses. In a framework of the VFMAS approach, our group and others have established methods for signal assignments, sensitivity enhancement, and structural elucidation for routine applications of 13C and 1H SSNMR analysis on unlabeled paramagnetic materials.. Potential targets of the applications include a wide variety of paramagnetic systems such as drugs, catalysts, coordination polymers, hemes, nanocomposites, and nanoparticles.30 These SSNMR studies on small paramagnetic systems stimulated recent progress in SSNMR of paramagnetic biomolecules.. We will discuss an approach for sensitivity enhancements in 13C cross polarization MASCPMASof hydrated proteins in microcrystals by 1H T1 reduction with paramagnetic ion doping and fast signal acquisition
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