Ensemble-docking with AutoDock4.2 and enhanced-sampling of Pocket Shape
VMD 1.9.3
Pymol 1.8.4
MGLTools 1.5.6
Amber18
Gromacs2016.5
R3.5.1
PLUMED2.4
AutoDock4.2
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 Gasteiger for docking
Ligand parameters and charges for docking (Gasteiger) derived using the MGLTools
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 95/100 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: 95/100 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 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.
Hybrid genetic algorithm with local search (GA-LS)
ga_num_evals 25000000 (default 2500000)
autodock_parameter_version 4.2 (AD4.1_bound.dat)
ga_run=1 # do this many hybrid GA-LS runs
grid spacing 0.25 Angstrom (default 0.375)
Ensemble-docking calculations were performed with AutoDock4.2, disallowing any flexibility of both ligands and receptors. Docking runs were executed with the above specified parameters while default values were applied for the rest of the variables. For each compound, 10 conformations and 200 receptor structures were employed in ensemble-docking runs. The top 5 clusters of poses from the docking (see above) are submitted with this protocol. After structural alignment of the binding sites of all generated complexes, the poses were clustered using a distance RMSD cutoff of 0.075 times the number Nha of heavy atoms of the ligand, in order to tune the cutoff the the size of the compound. Clusters were ordered according to the top score (lowest binding free energy) within each cluster.
No
Yes