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  NMR spectrometer  

Nuclear Magnetic Resonance(NMR) Spectroscopy

My primary research goals are to develop and apply methods to characterize and compare the structure of compounds using NMR spectroscopy. NMR is applicable to a wide range of materials, including gases, solutions, crystalline solids, amorphous materials and surfaces, and a large number of nuclear isotopes are available as spectroscopic probes, including 1H, 13C and 31P, and over 80 other NMR-accessible nuclei. The NMR experiment is very sensitive to subtle changes in the electronic or geometric environment around each nucleus, making NMR an ideal structural probe. Several specific areas of research are being actively pursued.

Gel-phase NMR of polymer-supported species

We are applying a combination of solid-state and solution NMR techniques in concert to permit in situ analyses of supported species. Application of special techniques such as magic angle spinning as well as refinement of some standard NMR experiments to the unique aspects of swollen resin gels have allowed us to obtain substantial improvements in suppression of background polymer signals as well as improved selectivity in multidimensional correlation techniques. One of the most successful areas to which high-resolution NMR has been applied is the determination of polypeptide structures in solution by multidimensional techniques such as TOCSY, NOESY and HMQC, thus our work using HRMAS NMR of solid-supported peptides is an important extension of the determination of peptide structures to include samples that are still attached to the polymer support. As one example of its utility, NMR spectroscopy of these samples is of interest because many solid-supported synthetic strategies encounter reaction difficulties, such as the so-called "difficult couplings" in peptide synthesis, where reaction efficiency drops precipitously at various stages of the solid-phase coupling reactions. It is believed that this is due to the formation of secondary structure by the growing peptide chain, although no direct evidence exists. Even if secondary structure is the culprit, it is unclear whether the coupling inefficiency results from direct blockage of the reaction site due to peptide folding, or from solvent inaccessibility due to an increase in polymer rigidity and concomitant "deswelling" of the resin. Clearly an in situ structure determination technique is needed, and the ability of NMR to contribute to this area is significant, with its ready application to solution, solid and semi-solids like membranes extensively documented in the past. We initiated studies on several known problematic peptide sequences, most notably acyl carrier peptide (ACP) on Wang resin, which is an established sequence used in testing for difficult couplings. We have found that pulse sequences such as TOCSY and ROESY provide particularly "clean" spectra of epitopes, clear of interfering correlations from background polymer signals. We have furthered this approach by using a TOCSY mixing sequence, DIPSI-2, in concert with a normal one-dimensional pulse-acquire sequence to remove, or at least substantially attenuate, the residual proton signal that arises from the polymer. Recently we have extended our spectroscopic tools by developing inverse-HMQC sequences tailored to the conditions encountered with these heterogeneous spinning samples. It is becoming increasingly clear through this work that the Fmoc protecting group is responsible for many of the interactions that appear spectroscopically when difficult couplings arise.

One novel approach we have recently developed is the use of the polymer support as an isolating medium for the individual peptide chains. A short sequence from the yeast prion protein Sup35 (Gly-Asn-Asn-Gln-Gln-Asn-Tyr) has been shown to produce fibrils typical of amyloidosis from solution; however, this very feature makes investigation of the isolated peptide chains impossible to determine in traditional solution experiments. By tethering this peptide chain to a polymer support, we are able to prevent aggregation from occurring, and have provided the first experimental evidence of at least one monomeric conformation.

  ROESY Gel-Phase NMR   GNNQQNY structure

Multiple-state structures of metal-containing compounds

NMR is unique in its ability to provide information concerning structure for molecules either dissolved in a solvent, fixed in a crystal lattice, trapped on a surface or isolated inside a cage or matrix. This information allows chemists to draw parallels between a crystal structure (determined by X-ray diffraction) and the "active" or chemically-reactive structure of a compound in solution or on a catalyst. My approach focuses on the metal centres in biological assemblies and heterogeneous catalysts, either by observing their NMR spectra directly or observing their effect on the NMR spectra of neighbouring nuclei. This information permits a rational approach for determining the complex molecular structures and comparing them to well-characterized crystalline materials, where the diffraction data permit a precise interpretation of the NMR spectra. For example, we are currently investigating vitamin B12 and its derivatives (the cobalamins) in an effort to characterize the structural changes they undergo in a variety of enzymatic pathways. The first step, depicted below, involved the determination of the magnitudes and orientations of the quadrupolar coupling and chemical shift interactions of 59Co in vitamin B12. By applying NMR to this study, we can obtain structural information without the need for single crystals, which is the only way this could be done using X-ray diffraction, the other common structural technique.

Top View

Side View

Top View of Cobalt Tensors in Vitamin B12 Side View of Cobalt Tensors in Vitamin B12

Solid-state NMR of quadrupolar nuclei

Nuclei with a nuclear spin I > 1/2 have a nuclear electric quadrupole moment which interacts with a surrounding electric field gradient to produce quadrupolar line-broadening. This feature, which is encountered in many multinuclear experiments, makes high-resolution solid-state NMR studies of these nuclei difficult. Another focus of my research is to use high-field NMR to reduce the limitations commonly encountered when attempting to study quadrupolar nuclei in solids. The principal goals are to devise methods to resolve chemically similar sites in materials in spite of the quadrupolar line-broadening, and to look beyond the quadrupolar interaction, to the chemical shielding interaction, for example, to learn more about the chemistry of the surroundings of these nuclei.

  Zn-67 NMR of Zinc Glycine complex  

Chemical shielding of metal nuclei

The different isotropic chemical shifts of nuclei such as 1H or 13C are associated with sites of different structures or "chemistry". Recent interest in chemical shielding has shifted to the chemical shielding tensor, since it is a more sensitive of the 3-d or anisotropic nature of the electronic environment around a nucleus. Little is known about the anisotropic shielding of the heavier nuclei, such as the transition metal nuclei 59Co and 67Zn, which happen to be quadrupolar as well. By characterizing the chemical shielding tensors of these nuclei in a variety of complexes, it will be possible to gain insight into the factors influencing their chemistry and bonding. The chemical shielding tensors can be determined either by directly observing the spread of chemical shifts in the solid state, or by measuring the magnetic field-dependent effect of anisotropic chemical shielding on the relaxation behaviour of these nuclei in solution.