J Chem Inf Model - CHARMM-GUI Ligand Binder for absolute binding free energy calculations and its application.


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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 set up 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 nonpolar 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). Therefore, CHARMM-GUI Ligand Binder provides a convenient and reliable way to set up the ligand binding free energy calculations and can be applicable to pharmaceutically important protein-ligand systems.

Resumo Limpo

advanc free energi perturb molecular dynam fepmd simul method avail accur calcul absolut bind free energi proteinligand complex howev method reli sever sophist command script implement various bias energi restraint enhanc converg fepmd calcul must handl proper yield correct result present userfriend web interfac charmmgui ligand binder httpwwwcharmmguiorginputgbind provid standard charmm input file calcul absolut bind free energi use fepmd simul number featur implement conveni set fepmd simul high customiz manner therebi permit acceler throughput import class comput decreas possibl human error interfac seri input file generat interfac test illustr calcul absolut bind free energi three nonpolar aromat ligand la mutant t lysozym three fkrelat ligand fkbp statist error within individu calcul found small kcalmol calcul bind free energi general agre well experiment measur previous comput studi within kcalmol therefor charmmgui ligand binder provid conveni reliabl way set ligand bind free energi calcul can applic pharmaceut import proteinligand system

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