HADDOCK2.2 protein-ligand refinement protocol
HADDOCK Webserver 2.2
OpenEye Omega 2018.Feb.1
OpenEye Shape 2018.Feb.1
OpenEye ROCS 3.2.2.2
ChemmineR 3.32.1
fmcsR 1.22
Assumed pH neutral
Protein charges from OPLS force field
Ligand parameters and charges from PRODRG
Templates were identified using the advanced search functionality of the RCSB PDB and the following settings: 95% sequence identity and presence of a ligand. No further modelling was performed on the 340 templates that were identified. A single receptor was used for the docking of each target ligand. The selection of the template for the docking was based on the similarity of the crystallographic ligand to the competition ligand as calculated by the MCS tanimoto index between every template ligand and the full competition set. The ligands were converted from SMILES format to 3D structures using OE-Omega and sampling up to 500 conformers per ligand. We selected 10 poses for docking based on the tanimoto-combo (shape + colour) similarity between the generated ligand poses and the selected (see above) template ligand. The selected ligand conformers were superimposed on the respective crystallographic ligands using the shape overlay functionality of the OE-Shape Toolkit.
Default HADDOCK2.2 server setting except for the following changes
randomization of starting orientations turned off
rigid body energy minimization turned off
delenph = False
initiosteps = 0
cool1_steps = 0
cool2_steps = 0
cool3_steps = 0
watersteps = 2500
w_vdw_0 = 1.0
w_elec_2 = 0.1
number of models for all stages = 200
RMSD clustering with a 2A cutoff
The docking was performed using the HADDOCK2.2 web server (van Zundert et al. J. Mol. Biol. 2015) using default parameters except for those specified above. Ensembles of 10 ligand structures and a single receptor were provided as input for ensemble refinement. The ligand was kept rigid for the entire duration of the refinement protocol.
The poses selected for submission are the top scoring poses of the clusters identified during the analysis of the it-water stage results. In the cases where only one cluster was identified the submission is made up of the top5 scoring models of that cluster. In all the other cases the submitted models are the top3 models of the top cluster and the top2 of the next best cluster. The clusters were sorted based on the average HADDOCK score of the top4 models of each cluster.
The scoring function used for ranking the poses is the standard HADDOCK score for the explicit solvent (water) refinement (It-water) which is defined as: HADDOCK-score = 1.0*Evdw + 0.1*Eelec + 1.0*Edesol, Edesol an empirical desolvation energy term (Fernandez-Recio et al. J. Mol. Biol. 2004). The intermolecular energies are calculated using the OPLS united atom force field parameters (Jorgensen, W. L. & Tirado-Rives. J. Am. Chem. Soc. 1988) for non-bonded atoms, using a 8.5 angstrom cut-off with a shifting function for the electrostatic energy and switching function between 6.5 and 8.5 angstrom for the van der Waals energy. For the electrostatics energy, a dielectric constant of 10 is used.
No
Yes