Using DNA oligonucleotides of different sequences as model systems, it is proposed to investigate the relationships between mismatches and the potentiality to assume double helical or hairpin structures. We plan to delineate the structures of hairpins and to determine the ideal length and sequence requirement for the formation of loops vis-a-vis double helixes. While mismatches can generate hairpin structural motifs. Poly(pyr).poly(pur) sequences have been claimed in the literature to take up such unusual structural exotics as non-ZDNA left- handed form and Hoogsteen G=C+ paired underwound right-handed form. Using synthetic poly(pyr).poly(pur) sequences, the true solution structures of such sequences will be determined. Structural factors associated with sequence directed bending will be delineated by determining the solution geometry of selected oligomers with sequences which are known to cause bending and related sequences which do not cause bending. Studies will be conducted using 2D-NMR spectroscopy at 500 MHz and allied spectroscopic tools. Structures will be derived either semiquantitatively using NOE distances and constructive engagement with theory and computer modelling. In a few cases structures will be derived quantitatively from the absolute magnitude of interproton distances from 2D NMR data collected under conditions in which spin diffusion effects will be eliminated or contained, and by the use of computer modelling for refinement. This proposal identifies some of the very stimulating current problems in the discipline as related to sequence directed structure and attempts to provide experimental design and strategy to solve them. One of the significant factors which contribute to the control of genomic expression must be structural. Hence, to understand the fundamental basis of the expression of cancer and other diseases, it is essential to know the detailed structural organization of the double helix, as driven by the sequence.
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