Rationalising sequence selection by ligand assemblies in the DNA minor groove: the case for thiazotropsin A

Hasan Y Alniss, Nahoum Guillaume Husan Anthony, Abedawn Khalaf, Simon Mackay, Colin Suckling, Roger Waigh, Nial Wheate, John Parkinson

Research output: Contribution to journalArticle

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Abstract

DNA-sequence and structure dependence on the formation of minor groove complexes at 5′-XCTAGY-3′ by the short lexitropsin thiazotropsin A are explored based on NMR spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD) and qualitative molecular modeling. The structure and solution behaviour of the complexes are similar whether X = A, T, C or G and Z = T, A, I or C, CCTAGI being thermodynamically the most favoured (ΔG = -11.1 ± 0.1 kcal.mol-1). Binding site selectivity observed by NMR for ACTAGT in the presence of TCTAGA when both accessible sequences are concatenated in a 15-mer DNA duplex construct is consistent with thermodynamic parameters (ΙΔGΙACTAGT > ΙΔGΙTCTAGA) measured separately for the binding sites and with predictions from modeling studies. Steric bulk in the minor groove for Y = G causes unfavourable ligand-DNA interactions reflected in lower Gibbs free energy of binding (ΔG = -8.5 ± 0.01 kcal.mol-1). ITC and CD data establish that thiazotropsin A binds the ODNs with binding constants between 106 and 108 M-1 and reveal that binding is driven enthalpically through hydrogen bond formation and van der Waals interactions. The consequences of these findings are considered with respect to ligand self-association and the energetics responsible for driving DNA recognition by small molecule DNA minor groove binders

LanguageEnglish
Pages711-722
Number of pages12
JournalChemical Science
Volume3
Issue number3
Early online date15 Dec 2011
DOIs
Publication statusPublished - 2012

Fingerprint

Ligands
DNA
Calorimetry
Titration
Binding Sites
Molecular modeling
DNA sequences
Gibbs free energy
Nuclear magnetic resonance spectroscopy
Binders
Hydrogen bonds
Nuclear magnetic resonance
Association reactions
Thermodynamics
Molecules
thiazotropsin A
lexitropsin

Keywords

  • rationalizing
  • sequence selection
  • ligand assemblies
  • DNA minor groove
  • thiazotropsin A

Cite this

Alniss, Hasan Y ; Anthony, Nahoum Guillaume Husan ; Khalaf, Abedawn ; Mackay, Simon ; Suckling, Colin ; Waigh, Roger ; Wheate, Nial ; Parkinson, John. / Rationalising sequence selection by ligand assemblies in the DNA minor groove : the case for thiazotropsin A. In: Chemical Science. 2012 ; Vol. 3, No. 3. pp. 711-722.
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Rationalising sequence selection by ligand assemblies in the DNA minor groove : the case for thiazotropsin A. / Alniss, Hasan Y; Anthony, Nahoum Guillaume Husan; Khalaf, Abedawn; Mackay, Simon; Suckling, Colin; Waigh, Roger; Wheate, Nial; Parkinson, John.

In: Chemical Science, Vol. 3, No. 3, 2012, p. 711-722.

Research output: Contribution to journalArticle

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AU - Alniss, Hasan Y

AU - Anthony, Nahoum Guillaume Husan

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AU - Mackay, Simon

AU - Suckling, Colin

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AU - Wheate, Nial

AU - Parkinson, John

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AB - DNA-sequence and structure dependence on the formation of minor groove complexes at 5′-XCTAGY-3′ by the short lexitropsin thiazotropsin A are explored based on NMR spectroscopy, isothermal titration calorimetry (ITC), circular dichroism (CD) and qualitative molecular modeling. The structure and solution behaviour of the complexes are similar whether X = A, T, C or G and Z = T, A, I or C, CCTAGI being thermodynamically the most favoured (ΔG = -11.1 ± 0.1 kcal.mol-1). Binding site selectivity observed by NMR for ACTAGT in the presence of TCTAGA when both accessible sequences are concatenated in a 15-mer DNA duplex construct is consistent with thermodynamic parameters (ΙΔGΙACTAGT > ΙΔGΙTCTAGA) measured separately for the binding sites and with predictions from modeling studies. Steric bulk in the minor groove for Y = G causes unfavourable ligand-DNA interactions reflected in lower Gibbs free energy of binding (ΔG = -8.5 ± 0.01 kcal.mol-1). ITC and CD data establish that thiazotropsin A binds the ODNs with binding constants between 106 and 108 M-1 and reveal that binding is driven enthalpically through hydrogen bond formation and van der Waals interactions. The consequences of these findings are considered with respect to ligand self-association and the energetics responsible for driving DNA recognition by small molecule DNA minor groove binders

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