Dependency of ligand free energy landscapes on charge parameters and solvent models |
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Authors: | Yuko Okamoto Toshimasa Tanaka Hironori Kokubo |
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Institution: | (1) Department of Physics, School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya Aichi, 464-8602, Japan;(2) Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 2-17-85 Juso-honmachi, Yodogawa-ku, Osaka 532-8686, Japan; |
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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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