System definition file¶
Although known previously as the receptor .prm file, the system definition
file has evolved to contain much more than the receptor information. The system
definition file is used to define:
Receptor input files and flexibility parameters (the section called Receptor definition)
Explicit solvent input file and flexibility parameters (the section called Solvent definition)
Ligand flexibility parameters (the section called Ligand definition).
External restraint terms to be added to the total scoring function (e.g. cavity restraint, pharmacophoric restraint)
Receptor definition¶
The receptor can be loaded from a single MOL2 file, or from a combination of
Charmm PSF and CRD files. In the former case the MOL2 file provides the topology
and reference coordinates simultaneously, whereas in the latter case the
topology is loaded from the PSF file and the reference coordinates from the CRD
file. For historical compatibility reasons, receptor definition parameters are
all defined in the top-level namespace and should not be placed between
SECTION / END_SECTION pairs.
Caution
If MOL2 and PSF/CRD parameters are defined together, the MOL2 parameters take precedence and are used to load the receptor model.
Parameter |
Description |
Type |
Default |
Range of values |
|---|---|---|---|---|
Parameters specific to loading receptor in MOL2 file format |
||||
|
Name of receptor MOL2 file |
Filename string |
No default value |
Valid MOL2 filename |
Parameters specific to loading receptor in Charmm PSF/CRD file format |
||||
|
Name of receptor Charmm PSF file |
Filename string |
No default value |
Valid Charmm PSF filename |
|
Name of receptor Charmm CRD file |
Filename string |
No default value |
Valid Charmm CRD filename |
|
Name of RxDock-annotated Charmm masses file |
Filename string |
No default value |
|
General receptor parameters, applicable to either file format |
||||
|
List of molecular segment names to read from either MOL2 or PSF/CRD file. If this parameter is defined, then any segment/chains not listed are not loaded. This provides a convenient way to remove cofactors, counterions and solvent without modifying the original file. |
Comma separated list of segment name strings (without any spaces) |
Empty (i.e. all segments read from file) |
Comma separated list of segment name strings |
|
Defines terminal OH and NH3+ groups withing this distance of docking volume as flexible. |
float (Angstroms) |
Undefined (rigid receptor) |
>0.0 (3.0 is a reasonable value) |
Advanced parameters (should not need to be changed by the user) |
||||
|
Disable the removal of explicit non-polar hydrogens from the receptor model. Not recommended |
boolean |
FALSE |
TRUE or FALSE |
|
Maximum mutation step size for receptor dihedral degrees of freedom. |
float (degrees) |
30.0 |
>0.0 |
Ligand definition¶
Ligand definition parameters need only be defined if you wish to introduce
tethering of some or all of the ligand degrees of freedom. If you are running
conventional free docking then this section is not required. All ligand
definition parameters should be defined in SECTION LIGAND. Note that the
ligand input SD file continues to be specified directly on the rbdock
command-line and not in the system definition file.
Parameter |
Description |
Type |
Default |
Range of values |
|---|---|---|---|---|
Main user parameters |
||||
|
Sampling mode for ligand translational degrees of freedom |
enumerated string literal |
|
|
|
Sampling mode for ligand whole-body rotational degrees of freedom |
enumerated string literal |
|
|
|
Sampling mode for ligand internal dihedral degrees of freedom |
enumerated string literal |
|
|
|
(for |
float (Angstroms) |
1.0 |
>0.0 |
|
(for |
float (degrees) |
30.0 |
>0.0–180.0 |
|
(for |
float (degrees) |
30.0 |
>0.0–180.0 |
Advanced parameters (should not need to be changed by the user) |
||||
|
Maximum mutation step size for ligand translational degrees of freedom |
float (Angstroms) |
2.0 |
>0.0 |
|
Maximum mutation step size for ligand whole-body rotational degrees of freedom |
float (degrees) |
30.0 |
>0.0 |
|
Maxium mutation step size for ligand internal dihedral degrees of freedom |
float (degrees) |
30.0 |
>0.0 |
Solvent definition¶
Solvent definition parameters need only be defined if you wish to introduce
explicit structural waters into the docking calculation, otherwise this section
is not required. All solvent definition parameters should be defined in
SECTION SOLVENT.
Parameter |
Description |
Type |
Default |
Range of values |
|---|---|---|---|---|
Main user parameters |
||||
|
Name of explicit solvent PDB file |
File name string |
No default value (mandatory parameter) |
Valid PDB filename |
|
Sampling mode for solvent translational degrees of freedom. If defined here, the value overrides the per-solvent translational sampling modes defined in the solvent PDB file |
enumerated string literal |
|
|
|
Sampling mode for solvent whole-body rotational degrees of freedom. If defined here, the value overrides the per-solvent rotational sampling modes defined in the solvent PDB file |
enumerated string literal |
|
|
|
(for |
float (Angstroms) |
1.0 |
>0.0 |
|
(for |
float (degrees) |
30.0 |
>0.0–180.0 |
|
Controls occupancy state sampling for all explicit solvent. If defined here, the values overrides the per-solvent occupancy states defined in the solvent PDB file |
float |
1.0 |
0.0–1.0 |
Advanced parameters (should not need to be changed by the user) |
||||
|
Maximum mutation step size for solvent translational degrees of freedom |
float (Angstroms) |
2.0 |
>0.0 |
|
Maximum mutation step size for solvent wholebody rotational degrees of freedom |
float (degrees) |
30.0 |
>0.0 |
|
Maximum mutation step size for solvent occupancy state degrees of freedom |
float (degrees) |
1.0 |
0.0–1.0 |
Solvent occupancy state sampling OCCUPANCY = 0 permanently disables all
solvent; OCCUPANCY = 1.0 permanently enables all solvent; OCCUPANCY
between 0 and 1 activates variable occupancy state sampling, where the value
represents the initial probability that the solvent molecule is enabled. For
example, OCCUPANCY = 0.5 means that the solvent is enabled in 50 % of the
initial GA population. However, the probability that the solvent is actually
enabled in the final docking solution will depend on the particular ligand, the
scoring function terms, and on the penalty for solvent binding. The occupancy
state chromosome value is managed as a continuous variable between 0.0 and 1.0,
with a nominal mutation step size of 1.0. Chromosome values lower than the
occupancy threshold (defined as 1.0 - OCCUPANCY) result in the solvent being
disabled; values higher than the threshold result in the solvent being enabled.
Cavity mapping¶
The cavity mapping section is mandatory. You should choose one of the mapping
algorithms shown below. All mapping parameters should be defined in
SECTION MAPPER.
Parameter |
Description |
Type |
Default |
Range of values |
|---|---|---|---|---|
Main user parameters |
||||
|
Mapping algorithm specifier |
string literal |
|
fixed |
|
(x,y,z) center of cavity mapping region |
Bracketed cartesian coordinate string (x,y,z) |
None |
None |
|
Radius of cavity mapping region |
float (Angstroms) |
10.0 |
>0.0 (10.0–20.0 suggested range) |
|
Radius of small probe |
float (Angstroms) |
1.5 |
>0.0 (1.0–2.0 suggested range) |
|
Radius of large probe |
float (Angstroms) |
4.0 |
> |
|
Maximum number of cavities to accept (in descending order of size) |
integer |
99 |
>0 |
Advanced parameters (less frequently changed by the user) |
||||
|
Receptor atom radius increment for excluded volume |
float (Angstroms) |
0.0 |
>=0.0 |
|
Grid resolution for mapping |
float (Angstroms) |
0.5 |
>0.0 (0.3–0.8 suggested range) |
|
Minimum cavity volume to accept (in Å3, not grid points) |
float (Angstroms3) |
100 |
>0 (100–300 suggested range) |
Parameter |
Description |
Type |
Default |
Range of values |
|---|---|---|---|---|
Main user parameters |
||||
|
Mapping algorithm specifier |
string literal |
|
fixed |
|
Reference ligand SD file name |
string |
|
None |
|
Radius of cavity mapping region |
float (Angstroms) |
10.0 |
>0.0 (10.0–20.0 suggested range) |
|
Radius of small probe |
float (Angstroms) |
1.5 |
>0.0 (1.0–2.0 suggested range) |
|
Radius of large probe |
float (Angstroms) |
4.0 |
> |
|
Maximum number of cavities to accept (in descending order of size) |
integer |
99 |
>0 |
Advanced parameters (less frequently changed by the user) |
||||
|
Receptor atom radius increment for excluded volume |
float (Angstroms) |
0.0 |
>=0.0 |
|
Grid resolution for mapping |
float (Angstroms) |
0.5 |
>0.0 (0.3–0.8 suggested range) |
|
Minimum cavity volume to accept (in Å3, not grid points) |
float (Å3) |
100 |
>0 (100–300 suggested range) |
Cavity restraint¶
The cavity restraint penalty function is mandatory and is designed to prevent
the ligand from exiting the docking site. The function is calculated over all
non-hydrogen atoms in the ligand (and over all explicit water oxygens that can
translate). The distance from each atom to the nearest cavity grid point is
calculated. If the distance exceeds the value of RMAX, a penalty is imposed
based on the value of (distance - RMAX). The penalty can be either linear or
quadratic depending on the value of the QUADRATIC parameter. It should not
be necessary to change any the parameters in this section. Note that the docking
protocol itself will manipulate the WEIGHT parameter, so any changes made to
WEIGHT will have no effect.
SECTION CAVITY
SCORING_FUNCTION RbtCavityGridSF
WEIGHT 1.0
RMAX 0.1
QUADRATIC FALSE
END_SECTION
Pharmacophore restraints¶
This section need only be defined if you wish to dock with pharmacophore
restraints. If you are running conventional free docking then this section is
not required. All pharmacophore definition parameters should be defined in
SECTION PHARMA.
Parameter |
Description |
Type |
Default |
Range of values |
|---|---|---|---|---|
|
Mandatory pharmacophore restraints file |
File name string |
None (mandatory parameter) |
Valid file name |
|
Optional pharmacophore restraints file |
File name string |
None (optional parameter) |
Valid file name, or empty |
|
Number of optional restraints that should be met |
Integer |
0 |
Between 0 and number of restraints in
|
|
Ligands with insufficient pharmacophore features to
match the mandatory restraints are always removed prior
to docking. If this parameter is true, the pre-filtered
ligands are written to an error SD file with the same
root name as the docked pose output SD file, but with
an |
Boolean |
FALSE |
TRUE of FALSE |
|
Overall weight for the pharmacophore penalty function |
Float |
1.0 |
>=0.0 |
Calculation of mandatory restraint penalty The list of ligand atoms that matches each restraint type in the mandatory restraints file is precalculated for each ligand as it is loaded. If the ligand contains insufficient features to satisfy all of the mandatory restraints the ligand is rejected and is not docked. Note that the rejection is based purely on feature counts and does not take into account the possible geometric arrangements of the features. Rejected ligands are optionally written to an error SD file. The penalty for each restraint is based on the distance from the nearest matching ligand atom to the pharmacophore restraint centre. If the distance is less than the defined tolerance (restraint sphere radius), the penalty is zero. If the distance is greater than the defined tolerance a quadratic penalty is applied, equal to (nearest distance - tolerance)2.
Calculation of optional restraint penalty The individual restraint penalties
for each restraint in the optional restraints file are calculated in the same
way as for the mandatory penalties. However, only the NOPT lowest scoring
(least penalised) restraints are summed for any given docking pose. Any
remaining higher scoring optional restraints are ignored and do not contribute
to the total pharmacophore restraint penalty.
Calculation of overall restraint penalty The overall pharmacophore restraint
penalty is the sum of the mandatory restraint penalties and the NOPT lowest
scoring optional restraint penalties, multiplied by the WEIGHT parameter
value.
NMR restraints¶
To be completed. However, this feature has rarely been used.
Example system definition files¶
Full system definition file with all sections and common parameters enumerated explicitly:
RBT PARAMETER_FILE_V1.00
TITLE HSP90-PU3-lig-cavity, solvent flex=5
RECEPTOR_FILE PROT_W3_flex.mol2
RECEPTOR_SEGMENT_NAME PROT
RECEPTOR_FLEX 3.0
SECTION SOLVENT
FILE PROT_W3_flex_5.pdb
TRANS_MODE TETHERED
ROT_MODE TETHERED
MAX_TRANS 1.0
MAX_ROT 30.0
OCCUPANCY 0.5
END_SECTION
SECTION_LIGAND
TRANS_MODE FREE
ROT_MODE FREE
DIHEDRAL_MODE FREE
MAX_TRANS 1.0
MAX_ROT 30.0
MAX_DIHEDRAL 30.0
END_SECTION
SECTION MAPPER
SITE_MAPPER RbtLigandSiteMapper
REF_MOL ref.sd
RADIUS 5.0
SMALL_SPHERE 1.0
MIN_VOLUME 100
MAX_CAVITIES 1
VOL_INCR 0.0
GRIDSTEP 0.5
END_SECTION
SECTION CAVITY
SCORING_FUNCTION RbtCavityGridSF
WEIGHT 1.0
END_SECTION
SECTION PHARMA
SCORING_FUNCTION RbtPharmaSF
WEIGHT 1.0
CONSTRAINTS_FILE mandatory.const
OPTIONAL FILE optional.const
NOPT 3
WRITE_ERRORS TRUE
END_SECTION
