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CHARMM-GUI Ligand Binder for Absolute Binding Free Energy Calculations and Its Application

Jo, Sunhwan
; 
Jiang, Wei
; 
Lee, Hui Sun
; 
Roux, Benoît
; 
Im, Wonpil
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Abstract
Advanced free energy perturbation molecular dynamics (FEP/MD) simulation methods are available to accurately calculate absolute binding free energies of protein-ligand complexes. However, these methods rely on several sophisticated command scripts implementing various biasing energy restraints to enhance the convergence of the FEP/MD calculations, which must all be handled properly to yield correct results. Here, we present a user-friendly web interface, CHARMM-GUI Ligand Binder (http://www.charmm-gui.org/input/gbinding), to provide standardized CHARMM input files for calculations of absolute binding free energies using the FEP/MD simulations. A number of features are implemented to conveniently setup the FEP/MD simulations in highly customizable manners, thereby permitting an accelerated throughput of this important class of computations while decreasing the possibility of human errors. The interface and a series of input files generated by the interface are tested with illustrative calculations of absolute binding free energies of three non-polar aromatic ligands to the L99A mutant of T4 lysozyme and three FK506-related ligands to FKBP12. Statistical errors within individual calculations are found to be small (~1 kcal/mol), and the calculated binding free energies generally agree well with the experimental measurements and the previous computational studies (within ~2 kcal/mol). CHARMM-GUI Ligand Binder provides a convenient and reliable way to setup the ligand binding free energy calculations and can be applicable to pharmaceutically important protein-ligand systems.
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Date
2013-01-28
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American Chemical Society
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Molecular Biosciences Scholarly Works
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Keywords
Free energy perturbation, Molecular dynamics, Protein-ligand Interactions, T4 Lysozyme, FKBP12
Citation
Jo, S., Jiang, W., Lee, H. S., Roux, B., & Im, W. (2013). CHARMM-GUI Ligand Binder for Absolute Binding Free Energy Calculations and Its Application. Journal of Chemical Information and Modeling, 53(1), 267–277. http://doi.org/10.1021/ci300505n
URI
https://hdl.handle.net/1808/24226
DOI
10.1021/ci300505n
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