HADDOCK2.2 protein-ligand ensemble-docking protocol with enhanced-sampling of Pocket Shape
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 AMBER-FB15 force field for MD simulations and from OPLS force field for docking
Ligand parameters and charges from PRODRG
The sequence given in "BACE_target_D3R_GC4.fasta" file was used to search for
structural templates in the pdb databank, using a threshold of 95% for the sequence identity and requiring the presence
of the word "BACE" in the title. The structure with PDB ID 1SGZ, free of any ligand, was thus selected as structural template.
Molecular dynamics simulations of the protein: standard MD simulations of 1 microsecond in length were performed with the pmemd
program of the amber18 suite, using a 0.15 M KCl water solution. The AMBER-FB15 force field with added atom types for amino
acid side chains was used for the protein, together with the TIP3P-FB water model and ions.
In addition, enhanced-sampling MD simulations (namely bias-exchange/well-tempered metadynamics) were performed using GROMACS2016.5
and the PLUMED2.4 plugin to enhance sampling of the putative binding site.
The latter was identified as the union of the binding pockets (residues within 3 Angstrom from the ligand) in experimental structures
with PDB IDs: 2IQG, 3DV1, 3DV5, 3K5C, 3VEU, 4DPI, 4KE1, 6BFD.
These in turn were identified using the advanced search functionality of the RCSB PDB and the following settings: 95% sequence identity
and presence of a ligand, which gave 340 templates. A single receptor was then selected for each target ligand, 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 set of 340 complexes. The selected ligand conformers were superimposed on the respective crystallographic ligands using the shape
overlay functionality of the OE-Shape Toolkit. The list of residues was then manually adjusted to keep the number around 20.
12 13 32 34 35 71 72 73 74 108 109 110 198 226 228 229 230 233 329 332.
Default HADDOCK2.2 server setting except for the following changes
w_vdw_0 = 0.0
w_elec_2 = 0.1
inter_rigid = 0.001
RMSD clustering with a 2A cutoff
number of it0, it1, water steps: 20000, 2000, 1000
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. For each compound, ensembles of 10 ligand structures and 200 receptor conformations were
provided as input. The poses selected for submission are the top scoring poses of the clusters identified during the analysis of the it-1
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 top1 models of the two next best clusters.
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 simulated annealing stage in torsional space (it1)
which is defined as: HADDOCK-score = 1.0*Evdw + 1.0*Eelec + 1.0*Edesol - 0.001*BSA, Edesol an empirical desolvation energy term
(Fernandez-Recio et al. J. Mol. Biol. 2004) and BSA the buried surface area. 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