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Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures.

Hunt RA, Munde M, Kumar A, Ismail MA, Farahat AA, Arafa RK, Say M, Batista-Parra A, Tevis D, Boykin DW, Wilson WD - Nucleic Acids Res. (2011)

Bottom Line: The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA.A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA.Similar, but generally smaller, effects are seen with TTTAA.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.

ABSTRACT
Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure.

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Related in: MedlinePlus

Histogram showing RL values for all compounds with AAAAA, ATATA, TTTAA and AAATT sequences. The blue represents AAAAA, red ATATA, the green TTTAA and the purple AAATT. Each group represents a structural group from Figure 1. All the data shown are for a 2:1 ratio of compound to binding site.
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Figure 5: Histogram showing RL values for all compounds with AAAAA, ATATA, TTTAA and AAATT sequences. The blue represents AAAAA, red ATATA, the green TTTAA and the purple AAATT. Each group represents a structural group from Figure 1. All the data shown are for a 2:1 ratio of compound to binding site.

Mentions: To assist in comparing results for different DNAs, all RL values were normalized by dividing them by the RL value of the free DNA, and the results are plotted in Figure 5. A compound with an RL value greater than 1 indicates the sequence had lower mobility than the free DNAs and is consistent with bending, while a value below one is consistent with straightening of the sequence. Interestingly, the ATATA sequence was bent by all compounds tested although the magnitude of bending varied with compound structures. DB921 and DB911 show the largest induced bending, followed by DB262 and DB75. All three of the monocations caused a small reduction of mobility and a small bend with the ATATA sequence.Figure 5.


Induced topological changes in DNA complexes: influence of DNA sequences and small molecule structures.

Hunt RA, Munde M, Kumar A, Ismail MA, Farahat AA, Arafa RK, Say M, Batista-Parra A, Tevis D, Boykin DW, Wilson WD - Nucleic Acids Res. (2011)

Histogram showing RL values for all compounds with AAAAA, ATATA, TTTAA and AAATT sequences. The blue represents AAAAA, red ATATA, the green TTTAA and the purple AAATT. Each group represents a structural group from Figure 1. All the data shown are for a 2:1 ratio of compound to binding site.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105405&req=5

Figure 5: Histogram showing RL values for all compounds with AAAAA, ATATA, TTTAA and AAATT sequences. The blue represents AAAAA, red ATATA, the green TTTAA and the purple AAATT. Each group represents a structural group from Figure 1. All the data shown are for a 2:1 ratio of compound to binding site.
Mentions: To assist in comparing results for different DNAs, all RL values were normalized by dividing them by the RL value of the free DNA, and the results are plotted in Figure 5. A compound with an RL value greater than 1 indicates the sequence had lower mobility than the free DNAs and is consistent with bending, while a value below one is consistent with straightening of the sequence. Interestingly, the ATATA sequence was bent by all compounds tested although the magnitude of bending varied with compound structures. DB921 and DB911 show the largest induced bending, followed by DB262 and DB75. All three of the monocations caused a small reduction of mobility and a small bend with the ATATA sequence.Figure 5.

Bottom Line: The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA.A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA.Similar, but generally smaller, effects are seen with TTTAA.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Georgia State University, Atlanta, GA 30302, USA.

ABSTRACT
Heterocyclic diamidines are compounds with antiparasitic properties that target the minor groove of kinetoplast DNA. The mechanism of action of these compounds is unknown, but topological changes to DNA structures are likely to be involved. In this study, we have developed a polyacrylamide gel electrophoresis-based screening method to determine topological effects of heterocyclic diamidines on four minor groove target sequences: AAAAA, TTTAA, AAATT and ATATA. The AAAAA and AAATT sequences have the largest intrinsic bend, whereas the TTTAA and ATATA sequences are relatively straight. The changes caused by binding of the compounds are sequence dependent, but generally the topological effects on AAAAA and AAATT are similar as are the effects on TTTAA and ATATA. A total of 13 compounds with a variety of structural differences were evaluated for topological changes to DNA. All compounds decrease the mobility of the ATATA sequence that is consistent with decreased minor groove width and bending of the relatively straight DNA into the minor groove. Similar, but generally smaller, effects are seen with TTTAA. The intrinsically bent AAAAA and AAATT sequences, which have more narrow minor grooves, have smaller mobility changes on binding that are consistent with increased or decreased bending depending on compound structure.

Show MeSH
Related in: MedlinePlus