Computational protocol: Application of the PM6 semi-empirical method to modeling proteins enhances docking accuracy of AutoDock

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[…] Crystal structures of the protein-ligand complexes used in this study were obtained from the Brookhaven Protein DataBank http://www.rcsb.org/pdb. When the asymmetric unit was found to differ from the biological unit, the ligand binding site was carefully checked. When the ligand was found to interact with more than one asymmetric units, the biological unit was used in the study (in cases of proteins with PDB code: 1OLU, 2XIS). Experimental binding affinities for the protein-ligand complexes were taken from the PDBBind Database []. The proteins and ligands used in this study were all formerly used as a test set in recently published papers [,] or were taken from the PDB core set []. The structures were chosen in order to meet the following criteria: structurally diverse ligands in complex with a heterogeneous collection of proteins; non-covalent binding between protein and ligand and crystallographic resolution lower than 3.2 Å.All docking studies described here involved flexible docking of the ligand to the rigid receptor, both of which were derived from the complex crystal structure. Input structures were prepared by using two different methods: (i), using Gasteiger charges for both the ligands and the proteins []; (ii), using PM6 charges calculated by MOPAC2009 [] for both the ligands and the proteins. Briefly, the input structures with Gasteiger charges were prepared as follows: The ligand atom types and bond types were assigned and hydrogens were added using AutoDockTools. Empirical charges were calculated with the method of Gasteiger []. For proteins, co-factors, such as HEME and metal ions were kept, and their atom types and bond types were assigned manually. Sulfate, halogens and water molecules were removed. Hydrogens were added in protein residues as well as Gasteiger partial charges using AutoDockTools. Non-polar hydrogens were merged and their charges were added to the heavy atoms. No additional optimization of the protein structures was carried out.Semi-empirical assignments were performed using the PM6 method by the Mozyme function of MOPAC2009 program [] integrated in Docking Server http://www.dockingserver.com. Ligand structures with semi-empirical charges were setup similarly as described above, except that in the last step PM6 charges were calculated using MOPAC2009 software. Protein structures were setup as follows: First, water molecules, sulfate, and halogens were removed. Hydrogen atoms were added to the pdb structures using AutoDockTools. The total charge of the protein and partial charges of the atoms were calculated by the Mozyme function of MOPAC2009 software. The calculated partial charges were applied for further calculations.Docking studies were subsequently performed using Docking Server http://www.dockingserver.com. Docking Server integrates Marvin http://www.chemaxon.com and MOPAC2009 during ligand set up in order to calculate partial charges at a given protonation state and for semi-empirical geometry optimization; and AutoDock 4 is integrated [] for docking calculation. In cases where protein and ligand partial charges were calculated with the PM6 method, the QASP parameter was modified (QASP = 0.00679) and used in Autogrid 4 and AutoDock 4 during docking calculations (see Results section for detailed explanation).Briefly, the following parameters were set in Docking Server: Grid parameter files were built and atom-specific affinity maps were constructed using Autogrid 4 []. These map files were generated using 60 × 60 × 60 grid points and 0.375 Å spacing, with the maps centered on the experimentally determined center of the bound ligand. Docking simulations for the study were carried out using the Lamarckian Genetic Algorithm. The initial position, orientation, and torsions of the ligand molecules were set randomly, and all rotatable torsions were released during docking. Each docking experiment was derived from 100 different runs that were set to terminate after a maximum of 2,500,000 energy evaluations and had a population size of 250. After each docking calculation, the RMSD between the lowest energy docked ligand pose and the complex crystal structure ligand pose was evaluated. […]

Pipeline specifications

Software tools AutoDock, DockingServer, Marvin
Applications Drug design, Protein interaction analysis
Organisms Dipturus trachyderma