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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM029787-16A2
Application #
3277430
Study Section
Molecular Cytology Study Section (CTY)
Project Start
1982-09-15
Project End
1992-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
16
Fiscal Year
1989
Total Cost
Indirect Cost
Name
State University of New York at Albany
Department
Type
Schools of Arts and Sciences
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12222
Ulyanov, N B; Sarma, M H; Zhurkin, V B et al. (1993) Decreased interstrand H2-H1' distance in the GC-rich part of the duplex d(CCTCAAACTCC).d(GGAGTTTGAGG) in solution at low temperature: proton nuclear magnetic resonance investigation. Biochemistry 32:6875-83
Ulyanov, N B; Gorin, A A; Zhurkin, V B et al. (1992) Systematic study of nuclear Overhauser effects vis-a-vis local helical parameters, sugar puckers, and glycosidic torsions in B DNA: insensitivity of NOE to local transitions in B DNA oligonucleotides due to internal structural compensations. Biochemistry 31:3918-30
Luo, J; Sarma, M H; Yuan, R D et al. (1992) NMR study of self-paired parallel duplex of d(AAAAACCCCC) in solution. FEBS Lett 306:223-8
Sarma, M H; Luo, J; Umemoto, K et al. (1992) Tetraplex formation of d(GGGGGTTTTT): 1H NMR study in solution. J Biomol Struct Dyn 9:1131-53
Umemoto, K; Sarma, M H; Gupta, G et al. (1990) Effect of the methyl group on DNA bending and curvature: structure of d(GA4U4C)2 in solution. Biochemistry 29:4714-22
Sarma, M H; Umemoto, K; Gupta, G et al. (1990) In search of a Hoogsteen base paired DNA duplex in aqueous solution. J Biomol Struct Dyn 8:461-82
Sarma, M H; Gupta, G; Garcia, A E et al. (1990) Quantitative structure of a complex between a minor-groove-specific drug and a bent DNA decamer duplex: use of 2D NMR data and NOESY constrained energy minimization. Biochemistry 29:4723-34
Sarma, M H; Gupta, G; Sarma, R H (1988) Structure of a bent DNA: two-dimensional NMR studies on d(GAAAATTTTC)2. Biochemistry 27:3423-32
Garcia, A E; Gupta, G; Sarma, M H et al. (1988) Stability and motion of a hairpin and the corresponding mismatched duplex: a theoretical exploration using molecular mechanics and normal mode analysis of 2D NMR results on d(GCCGCAGC). J Biomol Struct Dyn 6:525-42
Gupta, G; Sarma, M H; Sarma, R H (1988) On the question of DNA bending: two-dimensional NMR studies on d(GTTTTAAAAC)2 in solution. Biochemistry 27:7909-19

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