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Unformatted text preview: Protein- Ligand Binding Free Energy Calculation by the Smooth Reaction Path Generation (SRPG) Method Yoshifumi Fukunishi,* ,†,‡ Daisuke Mitomo, § and Haruki Nakamura †, | Biomedicinal Information Research Center (BIRC), National Institute of Advanced Industrial Science and Technology (AIST), 2-41-6, Aomi, Koto-ku, Tokyo 135-0064, Japan, Pharmaceutical Innovation Value Chain, BioGrid Center Kansai, 1-4-2 Shinsenri-Higashimachi, Toyonaka, Osaka 560-0082, Japan, Japan Biological Informatics Consortium (JBIC), 2-41-6, Aomi, Koto-ku, Tokyo 135-0064, Japan, and Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan Received June 16, 2009 We developed a new molecular dynamics simulation method for protein- ligand binding free energy calculation in an explicit water model. This method consists of three steps: (1) generation of a compound dissociation path starting from a stable protein- compound complex structure, (2) calculation of the free energy surface along the dissociation path, and (3) calculation of the free energy surface of a small area around the protein- compound complex structure, which is a free energy minimum. The protein- compound binding free energy is estimated from the information obtained by the above three steps. This method was applied to a small system, a 18-crown-6 ether with its ligand ion, and a realistic system consisting of a target protein with its inhibitor. This approximation worked well; the protein- inhibitor dissociation was successfully performed, and the binding free energies were calculated. 1. INTRODUCTION Estimation of protein- compound binding free energy ( ∆ G ) is important for structure-based drug development, and many protein- compound docking programs and scoring functions have been reported. 1- 7 The protein- compound docking programs and scoring functions are very fast computationally and, thus, are useful in in-silico (virtual) drug screening. However, the docking scores are not suf- ficiently precise to achieve the desired binding free energy error of 2- 3 kcal/mol. 8- 11 The molecular-mechanics Poisson- Boltzmann surface-area (MMPBSA) method 12,13 and the recent linear interaction energy (LIE) method 14- 18 have succeeded in reproducing the trend of ∆ G s for a single target protein. In the MMPBSA method, hydrophobic interaction, which is an entropy term, is evaluated by using the surface area, which provides only a rough, imprecise approximation. In the LIE method, the ∆ G is evaluated based on the enthalpy term. This term consists of the average van der Waals energy and average electrostatic energy. In the framework of statistical physics, the binding free energy is calculated based on the partition function of the system obtained from the canonical ensemble, which consists of numerous structures. The docking score, in contrast, is calculated based on a single structure of the system....
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This note was uploaded on 12/13/2010 for the course GENETIK 12 taught by Professor Atillabasar during the Spring '10 term at Istanbul Technical University.
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