Mechanistically, how do drugs and dyes intercalate into DNA? Do they intercalate directly into the A, B and Z structures -- or is there some other structural form for DNA into which drugs and dyes intercalate? We have proposed the existence of another DNA structure to be involved in the intercalation process. This structure -- called Beta DNA or Beta premelted DNA -- forms spontaneously in the centers of soliton-antisoliton (i.e., kink-antikink) bound states in DNA structure. Such structural solitons contain a modulated Beta alternation in sugar puckering about the central Beta premelted core region which gradually merges into B (or A) DNA on either side. We have called such composite structures -- Beta premeltons. We are uncertain, as yet, whether the centers of Beta premeltons are open enough to accomodate an intercalator directly -- however, structures such as these are known to have an intrinsic ability to undergo low frequency breather motions, and it is possible that such motions facilitate the intercalation process. We would like to provide direct X-ray crystallographic evidence for the existence of the Beta premelted structural form. This could be accomplished by crystallizing a series of suitable drug-oligonucleotide complexes, and then determining their three-dimensional structures by X-ray crystallography. Such structures could contain the Beta alternation in sugar puckering and demonstrate neighbor exclusion intercalative drug binding. In addition, we would like to crystallize the Beta premelton. Such a structure could be stabilized by binding actinomycin D to the center of a self-complementary double-stranded long chain oligonucleotide. If this can be crystallized, X-ray analysis could reveal the modulated Beta alternation in sugar puckering around the central Beta premelted core region merging into B (or A) DNA on either side. This would provide evidence supporting the model that has been proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM030032-04
Application #
3277654
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1981-08-01
Project End
1987-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
4
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Medicine
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627