Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 34, Issue 30, Pages 2601-2614Publisher
WILEY-BLACKWELL
DOI: 10.1002/jcc.23427
Keywords
replica-exchange umbrella sampling; replica exchange with solute tempering; molecular dynamics; protein-ligand binding; structure prediction; computer-aided drug design
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Takeda Pharmaceutical Co., Ltd. [25247071]
- Grants-in-Aid for Scientific Research [25102009, 25102001, 25247071] Funding Source: KAKEN
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We have developed a two-dimensional replica-exchange method for the prediction of protein-ligand binding structures. The first dimension is the umbrella sampling along the reaction coordinate, which is the distance between a protein binding pocket and a ligand. The second dimension is the solute tempering, in which the interaction between a ligand and a protein and water is weakened. The second dimension is introduced to make a ligand follow the umbrella potential more easily and enhance the binding events, which should improve the sampling efficiency. As test cases, we applied our method to two protein-ligand complex systems (MDM2 and HSP 90-alpha). Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank much faster with the improved sampling efficiency than the replica-exchange umbrella sampling method that we have previously developed. (c) 2013 Wiley Periodicals, Inc.
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