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Dependency of ligand free energy landscapes on charge parameters and solvent models

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Abstract

We performed replica-exchange molecular dynamics (REMD) simulations of six ligands to examine the dependency of their free energy landscapes on charge parameters and solvent models. Six different charge parameter sets for each ligand were first generated by RESP and AM1-BCC methods using three different conformations independently. RESP charges showed some conformational dependency. On the other hand, AM1-BCC charges did not show conformational dependency and well reproduced the overall trend of RESP charges. The free energy landscapes obtained from the REMD simulations of ligands in vacuum, Generalized-Born (GB), and TIP3P solutions were then analyzed. We found that even small charge differences can produce qualitatively different landscapes in vacuum condition, but the differences tend to be much smaller under GB and TIP3P conditions. The simulations in the GB model well reproduced the landscapes in the TIP3P model using only a fraction of the computational cost. The protein-bound ligand conformations were rarely the global minimum states, but similar conformations were found to exist in aqueous solution without proteins in regions close to the global minimum, local minimum or intermediate states.

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Acknowledgments

We are grateful for the insight, discussions and collegiality provided by Dr. Masaki Tomimoto. The authors also thank Dr. Douglas Cary for reading the manuscript. The simulations and computations were performed on the TSUBAME Grid Cluster at Global Scientific Information and Computing Center of Tokyo Institute of Technology supported by the MEXT Open Advanced Research Facilities Initiative. This work was supported, in part, by Grants-in-Aid for Scientific Research on Innovative Areas (“Fluctuations and Biological Functions”) and for the Next-Generation Super Computing Project, Nanoscience Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan.

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Authors and Affiliations

  1. Department of Physics, School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya, Aichi, 464-8602, Japan

    Yuko Okamoto

  2. Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 2-17-85 Juso-honmachi, Yodogawa-ku, Osaka, 532-8686, Japan

    Toshimasa Tanaka & Hironori Kokubo

Authors
  1. Yuko Okamoto
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  2. Toshimasa Tanaka
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  3. Hironori Kokubo
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Correspondence to Hironori Kokubo.

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Yuko Okamoto and Hironori Kokubo contributed equally to this work.

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Okamoto, Y., Tanaka, T. & Kokubo, H. Dependency of ligand free energy landscapes on charge parameters and solvent models. J Comput Aided Mol Des 24, 699–712 (2010). https://doi.org/10.1007/s10822-010-9367-z

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  • DOI: https://doi.org/10.1007/s10822-010-9367-z

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