Scoring Functions
DOCK uses several types of scoring functions to discriminate among orientations and molecules. Scoring is requested using the score_molecules parameter. A large portion of scoring functions can be called through descriptor score (but not all). Those with descriptor score functionality will be denoted in bold.
Contents
Continuous/DOCK Cartesian Energy Score
Continuous scoring may be used to evaluate a ligand:receptor complex without the investment of a grid calculation, or to perform a more detailed calculation without the numerical approximation of the grid. Continuous score is implemented under Descriptor Score as well. Continuous score is a cartesian based score and can be combined with other Cartesian based scores with very little computational expense.
Continuous/DCE Score Parameters
| Parameter | Description | Default Value |
|---|---|---|
| continuous_score_primary | Does the user want to perform continuous non-grid scoring as the primary scoring function? | no |
| continuous_score_secondary | Does the user want to perform continuous non-grid scoring as the secondary scoring function? | no |
| cont_score_rec_filename | File that contains receptor coordinates | receptor.mol2 |
| cont_score_att_exp | VDW Lennard-Jones potential attractive exponent | 6 |
| cont_score_rep_exp | VDW Lennard-Jones potential repulsive exponent | 12 |
| cont_score_rep_rad_scale | Scalar multiplier of the radii for the repulsive portion of the vdw energy component only | 1.0 |
| cont_score_use_dist_dep_dielectric | Distance dependent dielectric switch | yes |
| cont_score_dielectric | Dielectric constant for the electrostatic term | |
| cont_score_vdw_scale | Scalar multiplier of vdw energy component | 1 |
| cont_score_vdw_scale | Flag to turn off vdw portion of the scoring function when cont_score_vdw_scale=0 | yes |
| cont_score_es_scale | Scalar multiplier of electrostatic energy component | 1.0 |
| cont_score_turn_off_es | Flag to turn off es portion of the scoring function when cont_score_es_scale = 0 | yes |
Continuous/DCE Score Output Components
| Output Component | Description |
|---|---|
| Continuous_score | sum of the van der Waals and electrostatic interactions |
| Continuous_vdw_energy | VDW interaction between ligand and receptor |
| Continuous_es_energy | ES interaction between the ligand and receptor |
Grid-Based Score
DOCK needs a fast scoring function to evaluate poses rapidly during growth. The energy grid is used for this. The grid stores the non-bonded Molecular Mechanics Potential of the receptor at each grid point.
Grid can be called under descriptor score but it is suggested to not mix grid-based and cartesian space as that will dramatically increase computing time.
Grid Score Parameters
| Parameter | Description | Default Value |
|---|---|---|
| grid_score_primary | Does the user want to perform grid-based energy scoring as the primary scoring function? | yes- |
| grid_score_rep_rad_scale | Scalar multiplier of the radii for the repulsive portion of the VDW energy component only when grid score is turned on | 1.0 |
| grid_score_vdw_scale | Scalar multiplier of the VDW energy component | 1 |
| grid_score_turn_off_vdw | A flag to turn off vdw portion of scoring function when grid score vdw scale = 0 | yes |
| grid_score_es_scale | Flag to scale up or down the es portion of the scoring function when es scale is turned on | 1 |
| grid_score_turn_off_es | A flag to turn off es portion of scoring function when grid score es scale = 0 | yes |
| grid_score_grid_prefix | The prefix to the grid files containing the desired nrg/bmp grid | grid |
Grid Score Output Components
These values will be printed in the header of the mol2 file post DOCK process.
| Output Component | Description |
|---|---|
| Grid_score | Sum of the VDW and ES interactions |
| Grid_vdw_energy | VDW interaction between the ligand grid |
| Grid_es_energy | ES interaction betweent eh ligand and grid |
MultiGrid Score
The MultiGrid Score is similar to the Footprint Score described below, except that in the case of the Multi-Grid Score, the pair-wise interaction energies are computed over multiple grids rather than in Cartesian space. This is done to improve the tractability of FPS calculations as well as to make it simple to combine FPS and standard Grid Score. If the multiple grids are prepared as recommended than the sum of the interactions with each grid should equal the interaction of a standard DOCK grid representing the entire target. By default MultiGrid score will equal the sum of the interactions with all grids plus a FPS component generated by treating each grid as a protein residue. User defined scaling factors allow MultiGrid score to be set to equal Grid score, FPS score or any combination thereof. Generally, "important" receptor residues are identified before-hand based on the magnitude of their interaction with the reference ligand, then a unique grid is generated to represent each of those residues. Finally, a "remainder" grid is generated to represent all remaining receptor residues. The scoring function itself will then calculate intermolecular VDW and ES energies for the reference ligand and pose ligand on each of the grids (also called footprints), then it will calculate the footprint similarity using either the Standard Euclidean, Normalized Euclidean, or Pearson Correlation similarity metrics.
MultiGrid can be called under descriptor score but it is suggested to not mix grid-based and cartesian space as that will dramatically increase computing time.
MultiGrid Score Parameters
| Parameter | Description | Default Value |
|---|---|---|
| multigrid_score_primary | Does the user want to perform grid-based energy scoring as the primary scoring function? | yes- |
| multigrid_score_rep_rad_scale | Scalar multiplier of the radii for the repulsive portion of the VDW energy component only when grid score is turned on | 1.0 |
| multigrid_score_vdw_scale | Scalar multiplier of the VDW energy component | 1 |
| multigrid_score_es_scale | Flag to scale up or down the es portion of the scoring function when es scale is turned on | 1 |
| multigrid_score_number_of_grids | Path to the reference txt file - only used when footprint reference txt is turned on. | ligand_footprint.txt |
| multigrid_score_grid_prefix0 | Provide prefixes to identify the grids. Note that the first grid starts at '0'. The last grid should be the remainder grid. This must be done for each grid. | multigrid0 |
| multigrid_score_individual_rec_ensemble | Flag for individual receptor (standard) or multiple receptor (not implemented yet). | no |
| multigrid_score_weights_text | Flag for providing a textfile as input for the reference footprint. | no |
| multigrid_score_footprint_text | Name of the reference footprint input text file, when multigrid_score_weight_text is turned on. | reference.txt |
| multigrid_score_fp_ref_mol | Flag for providing a MOL2 as input for the reference footprint. | no |
| multigrid_score_footprint_ref | Name of the reference footprint input MOL2 file, when multigrid_score_fp_ref_mol is turned on. | reference.mol2 |
| multigrid_score_foot_compare_type | Footprint similarity calculation methods (Options: Euclidean, Pearson). If Pearson, the correlation coefficient as the metric to compare the footprints. When the value is 1 then there is perfect agreement between the two footprints. WHen the value is 0 then there is poor agreement between the two footprints. If Euclidean, the Euclidean distance as the metric to compare the footprints. When the value is 0 then there is perfect agreement btween the two footprints. As the agreement gets worse between the two footprints the value increases. | Euclidean |
| multigrid_score_normalize_foot | normalization is used only with Euclidean distance. | no |
| multigrid_score_vdw_euc_scale | Scaling factor for VDW term. when using euclidean | 1.0 |
| multigrid_score_es_euc_scale | Scaling factor for ES term when using euclidean | 1.0 |
| multigrid_score_vdw_norm_scale | Scaling factor for VDW term. euclidean and normalize | 10.0 |
| multigrid_score_es_norm_scale | Scaling factor for ES term. Flags if using Pearson Correlation similarity metric for footprint comparison. | 10.0 |
| multigrid_score_vdw_cor_scale | Scaling factor for VDW term | (-10.0) |
| multigrid_score_es_cor_scale | Scaling factor for ES term | (-10.0) |
MultiGrid Score Output Components
These values will be printed in the header of the mol2 file post DOCK process.
| Output Component | Description |
|---|---|
| MultiGrid_score | Sum of the VDW and ES interactions |
| MultiGrid_vdw_energy | VDW interaction between the ligand grid |
| MultiGrid_es_energy | ES interaction betweent eh ligand and grid |
| MGS_vdw+es_energy | sum of VDW and ES components |
| MGS_vdw_fps | VDW footprint similarity score |
| MGS_es_fps | ES footprint similarity score |
| MGS_vdw+es_fps | sum of VDW adn ES footprint similarity scores |
Footprint Similarity Score
The Footprint Similarity Score is a scoring function that calculates intermolecular hydrogen bonds and footprint comparisons, in addition to standard intermolecular energies (VDW and ES).
Intermolecular Energies (VDW, ES) are calculated the same way as in Continuous Score.
A geometric definition of Hydrogen bonds is employed. We define 3 atoms XD, HD, and XA as the heavy atom donor, donated hydrogen, and heavy atom acceptor, respectively. There is a hydrogen bond present if the following two conditions are met:
- The distance between HD and XA is less than or equal to 2.5 angstroms;
- The angle defined by XD, HD, and XA is between 120 and 180 degrees.
Footprints are a per-residue decomposition of interactions between the ligand and the receptor. This can be performed for all three terms VDW, ES, HB. Two footprints can be compared in three ways: Standard Euclidean, Normalized Euclidean, Pearson Correlation.
Footprints are used to gauge how similar two poses or two molecules are to one-another. For applications to virtual screening applications a reference is required.
There are to choices for a reference:
- One can give a mol2 file containing a reference molecule, and footprints will be calculated.
- One can pass a text file containing VDW, ES, and H-bond footprints.
There are different choices for selection of residues:
- All residues.
- Residues chosen using a threshold (union of the sets of reference and pose). The VDW, ES, and HB footprints may have different residues chosen in this case.
- Selected residues.
Note that for (2) and (3) the remaining residue interaction may be placed in a remainder value included in the footprint.
Footprint Similarity Score can be called under Descriptor Score.
Footprint Similarity Score Parameters
| Parameter | Description | Default Value |
|---|---|---|
| footprint_similarity_score_primary | Flag to perform footprint scoring as the primary scoring function | no |
| footprint_similarity_score_secondary | Flag to perform footprint scoring as the secondary scoring function. | no |
| fps_score_use_footprint_reference_mol2 | Use a molecule to calculate footprint reference. | no |
| fps_score_footprint_reference_mol2_filename | Path to the reference mol2 file - only used when footprint reference mol2 is turned on. | ligand_footprint.mol2 |
| fps_score_use_footprint_reference_txt | Use a pre-calculated footprint reference in text format. | no |
| fps_score_footprint_reference_txt_filename | Path to the reference txt file - only used when footprint reference txt is turned on. | ligand_footprint.txt |
| fps_score_foot_compare_type | Footprint similarity calculation methods (Options: Euclidean, Pearson). If Pearson, the correlation coefficient as the metric to compare the footprints. When the value is 1 then there is perfect agreement between the two footprints. WHen the value is 0 then there is poor agreement between the two footprints. If Euclidean, the Euclidean distance as the metric to compare the footprints. When the value is 0 then there is perfect agreement btween the two footprints. As the agreement gets worse between the two footprints the value increases. | Euclidean |
| fps_score_normalize_foot | normalization is used only with Euclidean distance. | no |
| fps_score_foot_comp_all_residue | If yes all residues are used for calculating the footprint. | yes |
| fps_score_choose_foot_range_type | User can use to determine the type of the range of the footprint by either specifying a residue range or defining a threshold. If specify_range, the user chooses to use a residue range and all footprints will be evaluated only on this residue range. First residue id = 1 not 0. If threshold, the user chose to use a residue range that is defined by only residues that have magnitudes that exceed the specified thresholds. (Options: specify_range, threshold) | specify_range |
| fps_score_vdw_threshold | Specify threshold for van der Waals energy, when threshold is turned on. | 1 |
| fps_score_es_threshold | Specify threshold for electrostatic energy, when threshold is turned on. | 1 |
| fps_score_hb_threshold | specify threshold for hydrogen bonds (integers). 0.5 means that all none zeros are used, when threshold is turned on. | 0.5 |
| fps_score_use_remainder | Interaction remainder is all remaining residues not included individually | yes |
| fps_score_rec_filename | File that contains receptor coordinates | receptor.mol2 |
| fps_score_att_exp | VDW Lennard-Jones potential attractive exponent | 6 |
| fps_score_rep_exp | VDW Lennard-Jones potential repulsive exponent | 12 |
| fps_score_rep_rad_scale | Scalar multiplier of the radii for the repulsive portion of the VDW energy component ONLY | 1 |
| fps_score_use_distance_dependent_dielectric | Distance dependent dielectric switch | yes |
| fps_score_dielectric | Dielectric constant for electrostatic term | 4.0 |
| fps_score_vdw_scale | Scalar multiplier of vdw energy component | 1 |
| fps_score_es_scale | Scalar multiplier of es energy component | 1 |
| fps_score_hb_scale | Scalar multiplier of hb energy component | 0 |
| fps_score_internal_scale | Scalar multiplier of internal energy component | 0 |
| fps_score_fp_vwd_scale | Scalar multiplier of vdw footprint component | 0 |
| fps_score_fp_es_scale | Scalar multiplier of es footprint component | 0 |
| fps_score_fp_hb_scale | Scalar multiplier of hb footprint component | 0 |
Footprint Similarity Score Output Components
| Output Component | Description |
|---|---|
| Footprint_similarity_score | sum of the van der Waals, electostatic, and hbond footprint similarity scores |
| FPS_vdw_energy | VDW interaction between ligand and receptor |
| FPS_es_energy | ES interaction between the ligand and receptor |
| FPS_num_hbond | number of hydrogen bonds |
| FPS_vdw+es_energy | sum of the van der Waals and electrostatic components |
| FPS_vdw_fps | vdw footprint similarity score |
| FPS_es_fps | ES footprint similarity score |
| FPS_hb_fps | hbond footprint similarity score |
| FPS_vdw_fp_numres | number of residues in the receptor considered during the calculation |
| FPS_es_fp_numres | number of residues in the receptor considered during the calculation |
| FPS_hb_fp_numres | number of residues in the receptor considered during the calculation |
Pharmacophore Matching Similarity Score
The Pharmacophore Matching Similarity score is a scoring function that calculates the level of pharmacophore overlap between a reference molecule and a candidate molecule in three dimensional space.The functional form for quantifying the pharmacophore overlap in a virtual screening experiment using DOCK, termed pharmacophore matching similarity (FMS), is as follows:
Pharmacophore Matching Similarity Score can be called under Descriptor Score.
Pharmacophore Matching Similarity Score Parameters
| Parameter | Description | Default Value |
|---|---|---|
| pharmacophore_score_primary | Flag to perform FMS scoring as the primary scoring function | no |
| fms_score_use_ref_mol2 | Use a molecule to calculate pharmacophore reference | no |
| fms_score_ref_mol2_filename | molecule reference input file name. | Ph4.mol2 |
| fms_score_use_ref_txt | Use a text format pharmacophore reference. | no |
| fms_score_ref_txt_filename | text reference input file name. | Ph4.txt |
| fms_score_write_reference_pharmacophore_mol2 | Flag to write the reference pharmacophore model as a mol2 output file. | no |
| fms_score_write_reference_ph4_txt | Flag to write the reference pharmacophore model as a txt output file. | no |
| fms_score_reference_output_mol2_filename | reference pharmacophore mol2 output file name. | ref_ph4.mol2 |
| fms_score_reference_output_txt_filename | Reference pharmacophore txt output file name. | ref_ph4.txt |
| fms_score_write_candidate_pharmacophore | Flag to write the candidate pharmacophore model as a mol2 output file. | no |
| fms_score_candidate_output_filename | Candidate pharmacophore output file name | cad_ph4.mol2 |
| fms_score_write_matched_pharmacophore | Flag to write the matched pharmacophore model as a mol2 output file. The matched pharmacophore model, which is consist of pharmacophore points well-matched to any reference pharmacophore point, is a subset of the candidate pharmacophore model. | no |
| fms_score_matched_output_filename | matched pharmacophore output file name. | mat_ph4.mol2 |
| fms_score_compare_type | Flag to determine comparison method between reference and candidate ph4. If overlap user is using a ligand-based reference for computing the FMS. When the value is 0 then there is a perfect overlap. When the value is negative then you have multi-matched ph4. When the value is positive then you have matches with residual. If compatible (This is under development and not currently available) user is using a receptor based reference for computing the FMS. When the value is X then there is a perfect overlap. When the value is Y then you have multi-matched ph4. When the value is Z then you have matches with residual.(Options: overlap, compatible) | overlap |
| fms_score_full_match | Flag to determine if full match is desired. Currently only full match is considered. | yes |
| fms_score_match_rate_weight | Specify the constant parameter k (weight on the match rate term) in FMS score | 5 |
| fms_score_match_proj_cutoff | Specify the scalar projection cutoff σ in the pharmacophore matching protocol. Default value cos(45 � ) ≈ 0.7071 corresponds to a vector angle cutoff of 45 � | 0.7071 |
| fms_score_max_score | Specify the FMS score value for pharmacophore model pairs with no matches. This maximum FMS score depends on k, r and σ. | 20 |
Descriptor Score
The Descriptor Score is a newly developed scoring function that is a linear combination of scoring functions that allows users to guide sampling and evaluate docked molecules with one or more scoring criteria that emphasize different properties of the molecule. Descriptor score, as defined above, is a linear combination of various existing and newly developed scoring functions of DOCK, in the following formula:
Here the total score can consist of different scoring functions including grid-based score, multigrid FPS score, continuous score, footprint score, pharmacophore matching similarity score, Tanimoto score, Hungarian matching similarity score and volume overlap score.
These scoring functions can be categorized into two groups, interaction-based scoring functions and similarity-based scoring functions.
Interaction-based scoring functions include grid score, multigrid FPS score, continuous score, and footprint score. These four scoring functions report the interaction energy between the ligand and the receptor in either Cartesian space (continuous score and footprint score) or grid space (grid score and multigrid FPS score), thus the program does not allow users to combine scoring functions from separate groups. Users can however combine continuous score and footprint score. (Grid score is inherently computed in multigrid FPS score, thus these two scores are typically not combined). Not choosing any of the interaction-based scoring function is also an option of using descriptor score.
Similarity-based scoring functions include pharmacophore matching similarity score, Tanimoto score, Hungarian matching similarity score, and volume overlap score. This set of scoring functions always require a reference for comparison, and user can choose any number of scoring functions from this group for the desired descriptor score formula.
