DNA Minor Groove Induced Dimerization of Heterocyclic Cations: Compound Structure, Binding Affinity, and Specificity for a TTAA Site

Manoj Munde, Arvind Kumar, Raja Nhili, Sabine Depauw, Marie Hélène David-Cordonnier, Mohamed A. Ismail, Chad E. Stephens, Abdelbasset A. Farahat, Adalgisa Batista-Parra, David W. Boykin, W. David Wilson

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

With the increasing number and variations of genome sequences available, control of gene expression with synthetic, cell-permeable molecules is within reach. The variety of sequence-specific binding agents is, however, still quite limited. Many minor groove binding agents selectivity recognize AT over GC sequences but have less ability to distinguish among different AT sequences. The goal with this article is to develop compounds that can bind selectively to different AT sequences. A number of studies indicate that AATT and TTAA sequences have significantly different physical and interaction properties and different requirements for minor groove recognition. Although it has been difficult to get minor groove binding at TTAA, DB293, a phenyl-furan-benzimidazole diamidine, was found to bind as a strong, cooperative dimer at TTAA but with no selectivity over AATT. In order to improve selectivity, we made modifications to each unit of DB293. Binding affinities and stoichiometries obtained from biosensor-surface plasmon resonance experiments show that DB1003, a furan-furan-benzimidazole diamidine, binds strongly to TTAA as a dimer and has selectivity (KTTAA/KAATT=6). CD and DNase I footprinting studies confirmed the preference of this compound for TTAA. In summary, (i) a favorable stacking surface provided by the pi system, (ii) H-bond donors to interact with TA base pairs at the floor of the groove provided by a benzimidazole (or indole) -NH and amidines, and (iii) appropriate curvature of the dimer complex to match the curvature of the minor groove play important roles in differentiating the TTAA and AATT minor grooves.

Original languageEnglish (US)
Pages (from-to)847-864
Number of pages18
JournalJournal of Molecular Biology
Volume402
Issue number5
DOIs
StatePublished - Oct 8 2010

Fingerprint

Heterocyclic Compounds
Dimerization
Pentamidine
Cations
CD-I
DNA
Amidines
Artificial Cells
Surface Plasmon Resonance
Deoxyribonuclease I
Biosensing Techniques
Base Pairing
Genome
Gene Expression
furan
benzimidazole
DB293

Keywords

  • Biosensor-SPR
  • Cooperative dimer
  • DNA
  • Sequence recognition
  • TTAA

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

DNA Minor Groove Induced Dimerization of Heterocyclic Cations : Compound Structure, Binding Affinity, and Specificity for a TTAA Site. / Munde, Manoj; Kumar, Arvind; Nhili, Raja; Depauw, Sabine; David-Cordonnier, Marie Hélène; Ismail, Mohamed A.; Stephens, Chad E.; Farahat, Abdelbasset A.; Batista-Parra, Adalgisa; Boykin, David W.; Wilson, W. David.

In: Journal of Molecular Biology, Vol. 402, No. 5, 08.10.2010, p. 847-864.

Research output: Contribution to journalArticle

Munde, M, Kumar, A, Nhili, R, Depauw, S, David-Cordonnier, MH, Ismail, MA, Stephens, CE, Farahat, AA, Batista-Parra, A, Boykin, DW & Wilson, WD 2010, 'DNA Minor Groove Induced Dimerization of Heterocyclic Cations: Compound Structure, Binding Affinity, and Specificity for a TTAA Site', Journal of Molecular Biology, vol. 402, no. 5, pp. 847-864. https://doi.org/10.1016/j.jmb.2010.08.018
Munde, Manoj ; Kumar, Arvind ; Nhili, Raja ; Depauw, Sabine ; David-Cordonnier, Marie Hélène ; Ismail, Mohamed A. ; Stephens, Chad E. ; Farahat, Abdelbasset A. ; Batista-Parra, Adalgisa ; Boykin, David W. ; Wilson, W. David. / DNA Minor Groove Induced Dimerization of Heterocyclic Cations : Compound Structure, Binding Affinity, and Specificity for a TTAA Site. In: Journal of Molecular Biology. 2010 ; Vol. 402, No. 5. pp. 847-864.
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AU - Depauw, Sabine

AU - David-Cordonnier, Marie Hélène

AU - Ismail, Mohamed A.

AU - Stephens, Chad E.

AU - Farahat, Abdelbasset A.

AU - Batista-Parra, Adalgisa

AU - Boykin, David W.

AU - Wilson, W. David

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