DOCK 6.10

This is a release of the version described in references [1] and [2] with
the new genetic algorithm DOCK_GA: molecular evolution for ligand design. 


NEW IN DOCK 6.10

DOCK_GA
    This new genetic algorithm leverages features of DOCK 6.9's de novo
    design and augments them to allow for crossover and mutation of molecules
    within an ensemble and allow for an ensemble to, by incremental changes,
    drive toward a greater degree of energetic fitness than the initial
    ensemble.  This enables efficient exploration of chemical space and provides
    opportunities for molecular refinement of promising ligands, including
    replacement of single segments/fragments within a molecule's interior.

Addition of Ramping for Virtual Screening Minimization
    A parameter was added for virtual screening experiments to the simplex
    minimizer (use_min_ramp_flex_growth) that will allow for less minimization
    steps at early layers, increasing the number of steps at each layer up to
    the user defined maximum. This saves time during docking and was not found
    to affect docking outcomes, but can be turned off by the user in the input.

Internal Energy Score
    The internal energy of a molecule can now be used as a score in DOCK, which
    allows structures to be minimized by the simplex minimizer. This means 
    conformations of ligands can be generated without protein influence, and 
    ligands can be constructed using de novo design in the same way.

De Novo Design - Molecular Weight Smoothing
    Previously in de novo design, any molecule above the molecular weight limit
    was rejected ("hard" pruning). A "soft" pruning function was added, and now
    when a molecule is written to file a user provided upper and lower molecular 
    weight limit can be assessed. Molecules can be rejected based on a Gaussian
    function with a user provided standard deviation.

Fragment Library Generation - Improved Visualization
    Previously, the default library generation procedure was saving
    untransformed coordinates of fragments to their respective output files
    after fragmentation.  Now, fragments are overlaid on top of each other as
    the default fragmentation behavior for easier viewing of fragment libraries.

Script for Postprocessing Truncation of Custom Fragment Libraries
    A python script was added to the DOCK suite of tools to allow for 
    postprocessing of fragment libraries to truncate the final library based on 
    a user-defined cutoff of fragment frequency. This will allow users to only 
    perform the relatively expensive fragmentation step once, and easily create 
    smaller libraries after.

Gzstream
    DOCK now has the ability to read in and write gzipped files using gzstream, 
    allowing us to leverage this space saving measure in future releases. 

Miscellaneous
   The parallel DOCK build mechanism generally supports any MPI installation;
   the focus on MPICH2 has been eliminated.

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DEPRECATED FEATURES

    1. Secondary scoring capabilities have been removed.

    2. PBSA Score has been removed.


~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

BUG FIXES

For DOCK:
    1. During DN and GA experiments, an error will now be thrown if VDW
    parameters that do not include information about dummy atoms are being
    used.  For these experiments, users should use vdw_de_novo.defn as their
    VDW parameters.

For Grid:
    1. Structures with nonintegral charges now return an error if any residue
    in the input has a nonintegral charge.  Users wishing to override this and
    still return a valid nonintegral-based grid can so specify in the grid
    input file with the parameter allow_non_integral_charges.

For accessories:
    1. Migrated from python 2 to 3.

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INPUT PARAMETER CHANGES AND THEIR DEFAULT VALUES

Example:
    parameter_name                      [default_value] (options):


Added:

For DOCK_GA:
    ga_molecule_file                    [ga_molecule_file.mol2] ():
    ga_utilities                        [no] (yes no):
    ga_fraglib_scaffold_file            [fraglib_scaffold.mol2] ():
    ga_fraglib_linker_file              [fraglib_linker.mol2] ():
    ga_fraglib_sidechain_file           [fraglib_sidechain.mol2] ():
    ga_torenv_table                     [fraglib_torenv.dat] ():
    ga_max_generations                  [100] ():
    ga_xover_on                         [yes] (yes no):
    ga_xover_sampling_method_rand       [yes] (yes no):
    ga_xover_max                        [150] ():
    ga_bond_tolerance                   [0.5] ():
    ga_angle_cutoff                     [0.14] ():
    ga_check_overlap                    [no] (yes no):
    ga_mutate_addition                  [yes] (yes no):
    ga_mutate_deletion                  [yes] (yes no):
    ga_mutate_substitution              [yes] (yes no):
    ga_mutate_replacement               [yes] (yes no):
    ga_mutate_parents                   [no] (yes no):
    ga_omut_rate                        [0.7] ():
    ga_max_mut_cycles                   [5] ():
    ga_mut_sampling_method              [rand] (rand | graph):
    ga_num_random_picks                 [15] ():
    ga_max_root_size                    [5] ():
    ga_energy_cutoff                    [100] ():
    ga_heur_unmatched_num               [1] ():
    ga_heur_matched_rmsd                [0.5] ():
    ga_constraint_mol_wt                [500] ():
    ga_constraint_rot_bon               [10] ():
    ga_constraint_H_accept              [10] ():
    ga_constraint_H_don                 [5] ():
    ga_constraint_formal_charge         [2] ():
    ga_ensemble_size                    [200] ():
    ga_selection_method                 [elitism] (elitism | tournament | roulette):
    ga_elitism_combined                 [yes] (yes no):
    ga_elitism_option                   [max] (percent | number | max):
    ga_max_num_gen_with_no_crossover    [25] ():
    ga_name_identifier                  [ga] ():
    ga_output_prefix                    [ga_output] ():

    ~With ga_mutate_parents set to "yes"~
    ga_pmut_rate                         [0.3] ():

    ~With ga_mut_sampling_method set to "graph"~
    ga_graph_max_picks                  [10] ():
    ga_graph_breadth                    [3] ():
    ga_graph_depth                      [2] ():
    ga_graph_temperature                [100] ():

    ~With ga_selection_method set to "tournament"~
    ga_tournament_p_vs_c                [yes] (yes no):

    ~With ga_selection_method set to "roulette"~
    ga_roulette_separate                [yes] (yes no):

    ~With ga_selection_method set to "elitism" and...~
    ~... ga_elitism_option set to "number"~
    ga_elitism_number                   [20] ():

    ~... ga_elitism_option set to "percent"
    ga_elitism_percent                  [0.2] ():

For DOCK_DN:
    dn_mol_wt_cutoff_type               [soft] ():
    dn_upper_constraint_mol_wt          [550] ():
    dn_lower_constraint_mol_wt          [0] ():
    dn_MW_std_dev                       [35] ():

For Scoring Functions:
    internal_energy_score_primary       [no] (yes no):

For Simplex Minimizer During Docking:

    use_min_ramp_flex_growth            [yes] (yes no):


Changed: 

Example
    parameter_name                      previous_value -> new_value


For Fragment Library Generation:
    
    fragment_library_trans_origin                   no -> yes

For DOCK_DN:
    
   dn_pruning_conformer_score_scaling_factor        1.0 -> 2.0

For Simplex Minimization
    
    simplex_grow_max_iterations                     500 -> 250

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

OUTPUT COMPONENTS

For DOCK_GA:
    1. ${ga_output_prefix}.restart0000.mol2 is the initial parent ensemble to 
    begin DOCK_GA sampling.

    2. ${ga_output_prefix}.restart####.mol2 is the molecules from each
    generation (####). This file can be used as a restart file where the user
    only needs to change simplex_random_seed to the number of the generation
    last completed.

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

KNOWN BUGS

    1. When selecting both internal energy and internal energy score, the
    parameter "internal_energy_rep_exp" appears twice in the question tree,
    and will be asked for user input if using DOCK from the command-line even
    if the value is already set.

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REFERENCES

1. Prentis, L.E.; Singleton, C.D.; Bickel, J.D.; Allen, W.J.; Rizzo, R.C.
A Molecular Evolution Algorithm for Ligand Design in DOCK. 
J. Comput. Chem. 43(29):1942-1963, 2022.

2. Singleton, C.D. (2018). Computer-aided Design of Fusion Inhibitors Targeting
Ebolavirus. Order No. 10746080, State University of New York at Stony Brook.