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

Witcha Treesuwan, Kitiyaporn Wittayanarakul, Nahoum G. Anthony, Guillaume Huchet, Hasan Alniss, Supa Hannongbua, Abedawn I. Khalaf, Colin J. Suckling, John A. Parkinson, Simon P. Mackay

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

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.
LanguageEnglish
Pages10682-10693
Number of pages12
JournalPhysical Chemistry Chemical Physics
Volume11
Issue number45
DOIs
Publication statusPublished - Aug 2009

Fingerprint

Free energy
deoxyribonucleic acid
free energy
Ligands
ligands
Enthalpy
DNA
Trajectories
simulation
Experiments
Calorimetry
Coulomb interactions
Complexation
Titration
Binders
Molecular dynamics
grooves
Entropy
field theory (physics)
Stabilization

Keywords

  • free energy study
  • 2
  • 1 ligand–DNA complex formation
  • pharmacology
  • binding thermodynamics

Cite this

Treesuwan, Witcha ; Wittayanarakul, Kitiyaporn ; Anthony, Nahoum G. ; Huchet, Guillaume ; Alniss, Hasan ; Hannongbua, Supa ; Khalaf, Abedawn I. ; Suckling, Colin J. ; Parkinson, John A. ; Mackay, Simon P. / A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation. In: Physical Chemistry Chemical Physics. 2009 ; Vol. 11, No. 45. pp. 10682-10693.
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A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation. / Treesuwan, Witcha; Wittayanarakul, Kitiyaporn; Anthony, Nahoum G.; Huchet, Guillaume; Alniss, Hasan; Hannongbua, Supa; Khalaf, Abedawn I.; Suckling, Colin J.; Parkinson, John A.; Mackay, Simon P.

In: Physical Chemistry Chemical Physics, Vol. 11, No. 45, 08.2009, p. 10682-10693.

Research output: Contribution to journalArticle

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AU - Treesuwan, Witcha

AU - Wittayanarakul, Kitiyaporn

AU - Anthony, Nahoum G.

AU - Huchet, Guillaume

AU - Alniss, Hasan

AU - Hannongbua, Supa

AU - Khalaf, Abedawn I.

AU - Suckling, Colin J.

AU - Parkinson, John A.

AU - Mackay, Simon P.

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JO - Physical Chemistry Chemical Physics

T2 - Physical Chemistry Chemical Physics

JF - Physical Chemistry Chemical Physics

SN - 1463-9076

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Treesuwan W, Wittayanarakul K, Anthony NG, Huchet G, Alniss H, Hannongbua S et al. A detailed binding free energy study of 2 : 1 ligand–DNA complex formation by experiment and simulation. Physical Chemistry Chemical Physics. 2009 Aug;11(45):10682-10693. https://doi.org/10.1039/b910574c