NMR-SOLVE

Fig. 21.9 NMR-SOLVE with DOXPR. A 2D [13C, HJ-HMQC spectrum recorded with a 75 pM (300 pM monomer) sample of U-2H, 13C/ H Thr,...

NMR-DOC (Nuclear Magnetic Resonance Docking of Compounds) 465 NMR-SOLVE... 

Sem, D.S., Yu, L., Coutts, S.M., and Jack, R. (2001) Object-oriented approach to drug design enabled by NMR SOLVE First real-time structural tool for characterizing protein-ligand interactions. J. Cell. Biochem. Suppl. 37, 99-105. 

Boden, M., Yuan, Z., Bailey, T.L. Prediction of protein continuum secondary structure with probabilistic models based on NMR solved structures. BMC Bioinformatics 2006, 7,68. 

I would like to thank Andrew, Lana, Brenda and Brent for making me feel part of the group and for many practical things during my stay in Halifax. I also owe much to Mike Lumsden, who solved many of the communication problems between me and the Bruker NMR apparatus. 

Because of the complexity of the polyether antibiotics tittle progress has been made in stmcture determination by the chemical degradation route. X-ray methods were the techniques most successfully applied for the early stmcture elucidations. Monensin, X206, lasalocid, lysocellin, and salinomycin were included in nineteen distinct polyether x-ray analyses reported in 1983 (190). Use of mass spectrometry (191), and H (192) and nmr (141) are also reviewed. More recently, innovative developments in these latter techniques have resulted in increased applications for stmcture determinations. Eor example, heteronuclear multiple bond connectivity (hmbc) and homonuclear Hartmann-Hahn spectroscopy were used to solve the stmcture of portimicin (14) (193). East atom bombardment mass spectrometry was used in solving the stmctures of maduramicin alpha and co-factors (58). 

In the structure sections, labelled compounds have often been used to solve a spectroscopic problem involved in microwave (Section 4.04.1.3.2), nitrogen NMR (Section 4.04.1.3.5), IR (Section 4.04.1.3.7(i)) or mass spectrometry (Section 4.04.1.3.8). The synthesis usually involves non-radioactive compounds ( H, N) by classical methods that must be repeated several times in order to obtain good yields. 

The methods discussed in this section extend the original concept of deriving structures from experimental NMR data in two ways. First, during the structure calculation, part of the assignment problem is solved automatically. This allows specification of the NOE data in a fonn closer to the raw data, which makes the refinement similar to X-ray refinement. Second, the quality of the data is assessed. The methods have been recently reviewed in more detail [64,67]. 

Einally, structural properties that depend directly neither on the data nor on the energy parameters can be checked by comparing the structures to statistics derived from a database of solved protein structures. PROCHECK-NMR and WHAT IE [94] use, e.g., statistics on backbone and side chain dihedral angles and on hydrogen bonds. PROSA [95] uses potentials of mean force derived from distributions of amino acid-amino acid distances. 

RA Laskowski, JAC Rullmann, MW MacArthur, R Kaptem, JM Thornton. AQUA and PRO-CHECK-NMR Programs for checking the quality of protein stiaictures solved by NMR. J Biomol NMR 8 477-486, 1996. 

Table 2.14. Suggested tactics for solving structures using NMR...

Correct structure proofs were earlier difficult to obtain, usually involving several reaction steps, and the structures were, therefore, assigned by analogy in many cases. However, through Raney nickel desulfurization (cf. Section VII,C), through NMR spectroscopy,and through polarographic analysis such problems are now easily solved. 

In the protein structure database PDB ( http //www. rcsb.org/pdb), by X-ray crystallography and NMR spectroscopy, experimentally solved 3D-protein structures are available to the public. Homology model building for a query sequence uses protein portions of known 3D-stmctures as structural templates for proteins with high sequence similarity. 

The incorporation of water in the structure of cellulose influences. Upon the hydrogen bond structure of the macromolecule. A great deal of work has been done in this area. Calorimetric methods have been invaluable in helping to solve the problem 23 It is, however evident that solid-state NMR spectroscopy may also give valuable information. 

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