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

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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

Original languageEnglish
Pages (from-to)711-722
Number of pages12
JournalChemical Science
Issue number3
Early online date15 Dec 2011
Publication statusPublished - 2012


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


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