DOCK 6.9 This is a release of the version described in reference [1] with the new ligand searching method DOCK_DN: De Novo design using fragment-based assembly. NEW IN DOCK 6.9 DOCK_DN for ligand de novo design: De novo design can be used to explore vast areas of chemical space in computational lead discovery. DOCK_DN is an iterative fragment growth method, integrated into the program DOCK, in which new molecules are built using rules for allowable connections based on known molecules. The method leverages DOCK's advanced scoring and pruning approaches, and users can define very specific criteria in terms of properties or features to customize growth toward a particular region. Refer to the user manual and reference 1. Fragment Library Generation: Users now have the ability to create fragment libraries from individual or multi-mol2 files. This function is important for utilizing any of the de novo ligand design algorithms. For more information please see the user manual. Mulitgrid Footprint: The footprint output text file (.txt) from multigrid now matches that of a Footprint text file from FPS. Old Reference.txt file format: ARG -0.061288 -1.156031 LYS -0.009564 -0.661054 ARG -0.316997 -1.903850 New Reference.txt file format: resname resid vdw_ref es_ref hb_ref vdw_pose es_pose hb_pose GLU 1 -0.000147 0.015721 0 -0.000143 0.015118 0 MET 2 -0.000380 0.005436 0 -0.000368 0.005407 0 GLU 3 -0.000199 0.195522 0 -0.000193 0.193527 0 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ DEPRECATED FEATURES 1. For a variety of reasons still under active development, amber_score cannot effectively be used as a secondary_score. This function was temporarily deprecated in 6.1, and using input parameter amber_score_secondary causes program termination. The recommended protocol is to perform two sequential DOCK runs where the output ligand poses from the first run are rescored specifying amber_score as the primary_score in the second run. 2. In order to minimize a ligand using the DOCK simplex minimizer a scoring function is needed, i.e., internal energy in combination with another scoring function is necessary. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ BUG FIXES Some bug reports have not yet been processed, but several important bugs have been fixed since the last release. For DOCK: 1. In terms of orienting Du placeholders can be used as critical points to increase the number of orients for smaller fragments/anchors. 2. Double bonds are no longer sampled in the DOCK simplex minimizer. 3. The current flex.defn file now includes single bonds between aromatic carbons, which will flag them as rotatable bonds. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ INPUT PARAMETER CHANGES AND THEIR DEFAULT VALUES Added: For Fragment Library Generation: write_fragment_libraries [no] (yes no): fragment_library_prefix [fraglib] (): fragment_library_freq_cutoff [1] (): fragment_library_sort_method [freq] (freq | fingerprint): fragment_library_trans_origin [no] (yes no): For DOCK_DN: dn_fraglib_scaffold_file [fraglib_scaffold.mol2] (): dn_fraglib_linker_file [fraglib_linker.mol2] (): dn_fraglib_sidechain_file [fraglib_sidechain.mol2] (): dn_user_specified_anchor [yes] (yes no): dn_fraglib_anchor_file [fraglib_anchor.mol2] (): dn_use_torenv_table [yes] (yes no): dn_torenv_table [fraglib_torenv.dat] (): dn_sampling_method [graph] (ex | rand | graph): dn_graph_max_picks [30] (): dn_graph_breadth [3] (): dn_graph_depth [2] (): dn_graph_temperature [100.0] (): dn_num_random_picks [20] (): dn_pruning_conformer_score_cutoff [100.0] (): dn_pruning_conformer_score_scaling_factor [1.0] (): dn_pruning_clustering_cutoff [100.0] (): dn_constraint_mol_wt [550.0] (): dn_constraint_rot_bon [15] (): dn_constraint_formal_charge [2.0] (): dn_heur_unmatched_num [1] (): dn_heur_matched_rmsd [2.0] (): dn_unique_anchors [1] (): dn_max_grow_layers [9] (): dn_max_root_size [25] (): dn_max_layer_size [25] (): dn_max_current_aps [5] (): dn_max_scaffolds_per_layer [1] (): dn_write_checkpoints [yes] (yes no): dn_write_prune_dump [no] (yes no): dn_write_orients [no] (yes no): dn_write_growth_trees [no] (yes no): dn_output_prefix [output] (): ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ OUTPUT COMPONENTS Added: For DOCK_DN: 1. ${dn_output_prefix}.denovo_build.mol2 is the mol2 file containing the complete top scoring molecules. Molecules are appended to this file as molecules are built to completion. 2. ${dn_output_prefix}.anchor_{#}.root_layer_{##}.mol2 are the partial molecules for each anchor (#) at each layer (##). These files are generated as the algorithm is running. This feature is turned on/off by the input parameter "dn_write_checkpoints". 3. ${dn_output_prefix}.anchor_{#}.prune_dump_layer_{##}.mol2 are the partial and complete molecules that were filtered out for having undesirable properties for each anchor (#) at each layer (##) of growth. This feature is turned on/off by the input parameter "dn_write_prune_dump". ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ FILE FORMAT CHANGES For DOCK: ########## DOCK_Rotatable_Bonds: ########## Molecular_Weight: ########## Formal_Charge: ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ KNOWN BUGS 1. When calculating rmsd without using a reference mol2 and turning on the ranking flag the associated rmsd values are calculated against the wrong molecules. Workaround: turn off ranking or use a reference mol2 file. 2. For a small portion of instances triple bonds next to rotatable bonds cause an issue upon initializing minimization. We are actively working on a solution to this bug. 3. Parallel runs may not be successful with earlier versions of MPI. DOCK6.9 was tested and validated using mainly 2018 MPI versions. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ RELEASE DATE November 2018 ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ REFERENCES 1. Allen, W. J.; Fochtman, B. C.; Balius, T. E.; Rizzo, R. C. Customizable de novo design strategies for DOCK: Application to HIVgp41 and other therapeutic targets. J. Comput. Chem. 2017, 38, 2641-2663. DOI: 10.1002/jcc.25052