MACROMOLECULAR STRUCTURE DETERMINATION BASED ON PARAMAGNETIC NMR SHIFTS

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We are studying well-resolved structure families for a DNA-drug-metal complex by making use of the pseudocontact shifts derived from the metal association in the structure calculation. We are currently assessing methods for obtaining the susceptibility tensor parameters independently of a structure and refining that tensor during the overall structural refinement. The tensor is a crucial component in the structural analysis, being required to interpret the shifts in terms of molecular structure. We have successfully shown that the tensor can be obtained independently or derived by refinement in a structure calculation. A comparison of our final structure with that obtained several years earlier by standard NMR methods reveals a substantial difference in the degree of distortion of the DNA caused by drug binding. We do not observe the base pair distortion and axis curvature that was reported in the earlier structure. Instead, the DNA appears to accomodate the drug by little more than an S-shaped bend in the helix axis and a widening of the minor groove to accomodate the drug. We have displayed and matched structures, calculated root mean square deviations, and generated a myriad of images representing different facets of the project. We have used the ability of MidasPlus to overlay different pdb files and to handle very large pdb files to understand characteristics of our shift based structures.