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A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation

Treesuwan, Witcha and Wittayanarakul, Kitiyaporn and Anthony, Nahoum G. and Huchet, Guillaume and Alniss, Hasan and Hannongbua, Supa and Khalaf, Abedawn I. and Suckling, Colin J. and Parkinson, John A. and Mackay, Simon P. (2009) A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation. Physical Chemistry Chemical Physics, 11 (45). pp. 10682-10693. ISSN 1463-9076

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    In 2004, we used NMR to solve the structure of the minor groove binder thiazotropsin A bound in a 2 : 1 complex to the DNA duplex, d(CGACTAGTCG)2. In this current work, we have combined theory and experiment to confirm the binding thermodynamics of this system. Molecular dynamics simulations that use polarizable or non-polarizable force fields with single and separate trajectory approaches have been used to explore complexation at the molecular level. We have shown that the binding process invokes large conformational changes in both the receptor and ligand, which is reflected by large adaptation energies. This is compensated for by the net binding free energy, which is enthalpy driven and entropically opposed. Such a conformational change upon binding directly impacts on how the process must be simulated in order to yield accurate results. Our MM-PBSA binding calculations from snapshots obtained from MD simulations of the polarizable force field using separate trajectories yield an absolute binding free energy (-15.4 kcal mol-1) very close to that determined by isothermal titration calorimetry (-10.2 kcal mol-1). Analysis of the major energy components reveals that favorable non-bonded van der Waals and electrostatic interactions contribute predominantly to the enthalpy term, whilst the unfavorable entropy appears to be driven by stabilization of the complex and the associated loss of conformational freedom. Our results have led to a deeper understanding of the nature of side-by-side minor groove ligand binding, which has significant implications for structure-based ligand development.

    Item type: Article
    ID code: 13195
    Keywords: free energy study, 2, 1 ligand–DNA complex formation, pharmacology, binding thermodynamics, Therapeutics. Pharmacology, Pharmacy and materia medica, Microbiology, Physics and Astronomy(all), Physical and Theoretical Chemistry
    Subjects: Medicine > Therapeutics. Pharmacology
    Medicine > Pharmacy and materia medica
    Science > Microbiology
    Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Faculty of Science > Pure and Applied Chemistry
    Related URLs:
      Depositing user: Ms Ann Barker-Myles
      Date Deposited: 12 Oct 2009 16:17
      Last modified: 05 Sep 2014 00:02

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