Relaxation cross-correlated

Elucidation of the stereostructure - configuration and conformation - is the next step in structural analysis. Three main parameters are used to elucidate the stereochemistry. Scalar coupling constants (mainly vicinal couplings) provide informa-hon about dihedral bond angles within a structure. Another way to obtain this information is the use of cross-correlated relaxation (CCR), but this is rarely used for drug or drug-like molecules. 

Fig. 9.10 (A) Definition of the dihedral angle d between the spin-pairs ij and k,l. (B) Cross-correlated relaxation can be detected by differences in intensities of the multiplet components of double quantum coherences...

Reif, B., Steinhagen, H., Junker, B., Reggelin, M., Griesinger, C. Determination of the orientation of a distant bond vector in a molecular reference frame by cross-correlated relaxation of nuclear spins. 

Brutscher, B. Prindples and applications of cross-correlated relaxation in biomolecules. Concepts. Magn. Reson. 2000, 12, 207-229. 

W. Transferred cross-correlated relaxation complements transferred NOE structure of an IL-4R-derived peptide bound to STAT-6. J. Am. Chem. Soc. 1999, 121, 1949-1953. 

Carlomagno, T., Sanchez, V. M., Blommers, M. J. )., Griesinger, C. Derivation of dihedral angles from CH-CH dipolar-dipolar cross-correlated relaxation rates a C-C torsion involving a quaternary carbon atom in epothilone A bound to tubulin. Angew. Chem. Int. Ed. 2003, 42, 2515-2517. 

To this end, Ilin et al. have developed the T-HMBC experiment,120 which is itself based on an experiment developed by Vincent and Zwahlen for measuring dipole-dipole cross-correlation in polysaccharides.121 These experiments allow determining the conformation around glycosidic bonds based on 3Jch couplings and C-H-dipolar cross-correlated relaxation. 

A new NMR method for the determination of the anomeric configuration in mono- and disaccharides has been described.18 The protocol is based on the different cross-correlated relaxation between proton chemical shift anisotropy (CSA) and dipolar relaxation for the a and (3 anomers of sugars. Only the ot-anomers show the presence of CSA (HI or Hl )-proton dipole (H1-H2 or Hl -H2 ) in the longitudinal relaxation of the anomeric protons. The method is of special interest for cases in which vicinal coupling constants between HI and H2 in both anomers a and (3 are similar and small, such as D-mannose, and the non-ambiguous description of the anomeric configuration needs additional measurements. 

The hydrogen bond length in Watson-Crick base pairs can be characterized using the recently developed method of measuring the cross-correlated relaxation [61] between H chemical shift anisotropy and dipole-dipole coupling of H and its hydrogen bond donor... 

N. Using the two measured cross-correlated relaxation rates, an apparent hydrogen bond length can be determined. Data for the 15N3-1H3...15N1 hydrogen bond in A-T base pairs of Antennapedia homeodomain DNA complex with a correlation time of 20 ns has been presented. 

The DD-CSA cross-correlated relaxation, namely that between 13C-1H dipole and 31P-CSA, can also be used to determine backbone a and C angles in RNA [65]. The experiment requires oligonucleotides that are 13C-labeled in the sugar moiety. First, 1H-coupled, / - DQ//Q-II CP spectra are measured. DQ and ZQ spectra are obtained by linear combinations of four subspectra recorded for each q-increment. Then, the cross-relaxation rates are calculated from the peak intensity ratios of the doublets in the DQ and ZQ spectra. The observed cross-correlation rates depend on the relative orientations of CH dipoles with respect to the components of the 31P chemical shift tensor. As the components of the 31P chemical shift tensor in RNA are not known, the barium salt of diethyl phosphate was used as a model compound with the principal components values of -76 ppm, -16 ppm and 103 ppm, respectively [106]. Since the measured cross-correlation rates are a function of the angles / and e as well, these angles need to be determined independently using 3/(H, P) and 3/(C, P) coupling constants. 

Fig. 7.1 Flow chart for structure determination with NMR, focusing on the most useful structural NMR parameters NOE,J coupling, dipolar coupling, cross-correlated relaxation rate, and chemical shifts.

Cross-Correlated Relaxation for the Measurement of Projection Angles between Tensors I 161... 

The cross-correlated relaxation rate observed for double- or zero-quantum coherence involving A1 or A2 and B1 or B2 for two dipolar interactions therefore takes the following form ... 

The characterisation of the angular dependence of the interaction of two dipole tensors A1 A2 and B B2 is therefore straightforward, namely it depends on the projection angle of the two bonds between A1 and A2 and between B1 and B2. The orientation and magnitude of the chemical shift anisotropy (CSA) tensor, which also can cause cross-correlated relaxation, is not know a priori and therefore needs to be determined experimentally or... 

To illustrate how cross-correlated relaxation can be used to measure the angle between two bond vectors, we will use the example of the generation of double and zero quantum coherence between spins A1 and B1 and call the angle between the Ax-A2 and B1-B2 vectors 8 (Fig. 7.18). 

For the measurement of cross-correlated relaxation rates, there are mainly three methods that have been used in practice. In the /-resolved constant time experiment, the multiplet Hnes exhibiting differential relaxation are resolved by the f couplings, and the line width is translated into intensity in a constant time experiment (Fig. 7.19a,d). In the J-resolved real time experiment the line width of each multiplet line is measured instead (Fig. 7.19b, d). This experiment has been applied so far only for the measurement of... 

Fig. 7.19 Three approaches to the measurement of dipole/dipole and dipole/ CSA cross-correlated relaxation rates.

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