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Pharmaceuticals 2012, 5(10), 1064-1079; doi:10.3390/ph5101064

Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation

1
Biological Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26, Aomi, Koto-ku, Tokyo 135-0064, Japan
2
Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan
*
Author to whom correspondence should be addressed.
Received: 29 August 2012 / Revised: 19 September 2012 / Accepted: 21 September 2012 / Published: 28 September 2012
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Abstract

We have developed a method for estimating protein-ligand binding free energy (DG) based on the direct protein-ligand interaction obtained by a molecular dynamics simulation. Using this method, we estimated the DG value statistically by the average values of the van der Waals and electrostatic interactions between each amino acid of the target protein and the ligand molecule. In addition, we introduced fluctuations in the accessible surface area (ASA) and dihedral angles of the protein-ligand complex system as the entropy terms of the DG estimation. The present method included the fluctuation term of structural change of the protein and the effective dielectric constant. We applied this method to 34 protein-ligand complex structures. As a result, the correlation coefficient between the experimental and calculated DG values was 0.81, and the average error of DG was 1.2 kcal/mol with the use of the fixed parameters. These results were obtained from a 2 nsec molecular dynamics simulation.
Keywords: protein-ligand docking; molecular dynamics simulation; protein-ligand binding free energy protein-ligand docking; molecular dynamics simulation; protein-ligand binding free energy
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Fukunishi, Y.; Nakamura, H. Statistical Estimation of the Protein-Ligand Binding Free Energy Based On Direct Protein-Ligand Interaction Obtained by Molecular Dynamics Simulation. Pharmaceuticals 2012, 5, 1064-1079.

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