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

Alniss, Hasan Y and Anthony, Nahoum Guillaume Husan and Khalaf, Abedawn and Mackay, Simon and Suckling, Colin and Waigh, Roger and Wheate, Nial and Parkinson, John (2012) Rationalising sequence selection by ligand assemblies in the DNA minor groove : the case for thiazotropsin A. Chemical Science, 3 (3). pp. 711-722. ISSN 2041-6520

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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

    Author(s):Alniss, Hasan Y, Anthony, Nahoum Guillaume Husan ORCID logoORCID: https://orcid.org/0000-0002-2026-8763, Khalaf, Abedawn ORCID logoORCID: https://orcid.org/0000-0001-9162-7527, Mackay, Simon ORCID logoORCID: https://orcid.org/0000-0001-8000-6557, Suckling, Colin, Waigh, Roger, Wheate, Nial and Parkinson, John ORCID logoORCID: https://orcid.org/0000-0003-4270-6135
    Item type:Article
    ID code:42310
    Keywords:rationalizing , sequence selection , ligand assemblies , DNA minor groove , thiazotropsin A, Chemistry, Pharmacy and materia medica, Chemistry(all)
    Subjects:Science > Chemistry
    Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Faculty of Science > Pure and Applied Chemistry
    Depositing user: Pure Administrator
    Date deposited:07 Dec 2012 15:12
    Last modified:26 Jan 2020 01:43
    URI:https://strathprints.strath.ac.uk/id/eprint/42310
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