A Detailed Binding Free Energy Study Of 2 : 1 Ligand–DNA Complex Formation By Experiment And Simulation

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Journal Title, Volume, Page: 
Physical Chemistry Chemical Physics, 2009,11, 10682-10693 DOI: 10.1039/B910574C
Year of Publication: 
2009
Authors: 
Witcha Treesuwan
Chemistry Department and Center of Nanotechnology, Kasetsart University, Bangkok 10900, Thailand
Kitiyaporn Wittayanarakul
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, UK
Nahoum G. Anthony
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, UK
Guillaume Huchet
Chemistry Department and Center of Nanotechnology, Kasetsart University, Bangkok 10900, Thailand
Hasan Alniss
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, UK
Current Affiliation: 
Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine
Supa Hannongbua
Chemistry Department and Center of Nanotechnology, Kasetsart University, Bangkok 10900, Thailand
Abedawn I. Khalaf
WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK
Colin J. Suckling
WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK
John A. Parkinson
WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK
Simon P. Mackay
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, UK
Preferred Abstract (Original): 

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.