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FRED can optionally restrict the poses it will examine during the exhaustive docking step to poses that match user defined constraints. Constraint information (if present) is contained in the receptor file.
Protein constraints can only be setup with the fred_receptor GUI program. The fred_receptor GUI can also add/remove/modify constraints on existing receptor files.
Custom constraints can be added/created/removed with the fred_receptor GUI, but can also be added to a receptor on the command line using the -pharm flag to pass a constraint file. The format of this file is described in the -pharm flag documentation. If a receptor file with existing custom constraints is passed to FRED and the -pharm flag is used the constraints in the receptor file will be ignored and the constraints in the -pharm file will be used.
This subsection has several examples of constraint files that demonstrate some subtleties of the constraint files.
The following constraint file which would be passed to the -pharm parameter, specifies a single constraint with no SMARTS pattern.
SPHERE 1 4.0 10.0 10.0 10.0
This tells FRED that custom constraint feature '1' has a sphere associated with it. The sphere is radius 4.0 and is centered at the coordinate (10.0,10.0,10.0). With this file every potential pose that FRED examines will be rejected unless the pose has at least 1 heavy atom within 4.0 Angstroms of the coordinate (10.0,10.0,10.0). A feature can have more than one sphere as in the following example.
The following constraint file specifies two constraints, only one of which need be satisfied.
SPHERE 1 4.0 10.0 10.0 10.0 SPHERE 1 3.0 9.0 12.0 8.0
This tells FRED that custom constrain feature '1' has two spheres associated with it. The effect is that every pose must have at least one heavy atom that is either within 4.0 Angstroms of (10.0,10.0,10.0) OR within 3.0 Angstroms of (9.0,12.0,8.0). This is different than the following.
The following constraint file specifies two constraints, both of which must be satisfied.
SPHERE 1 4.0 10.0 10.0 10.0 SPHERE 2 3.0 9.0 12.0 8.0
This would tell FRED to create two custom constraint features, '1' and '2', both of which must be satisfied. The effect here is that every pose must have at least one heavy atom within 4.0 Angstroms of (10.0,10.0,10.0) AND at least one heavy atom within 3.0 Angstroms of (9.0,12.0,8.0).
By default any heavy atom on the ligand can satisfy a custom constraint feature. Supplying a SMARTS pattern along with the sphere definition will ensure that only poses that can place at least one atom of that pattern within the sphere will satisfy the constraint. This is illustrated in the following example.
The following constraint file specifies a location and a SMARTS pattern.
SPHERE 1 4.0 10.0 10.0 10.0 SMARTS 1 F
This tells FRED that every pose must have at least one fluorine atom that is within 4.0 Angstroms of (10.0,10.0,10.0).
SPHERE 1 4.0 10.0 10.0 10.0 SMARTS 1 F SPHERE 2 5.0 0.0 0.0 0.0 SMARTS 2 C=O SPHERE 3 3.0 -10.0 -10.0 -10.0 SPHERE 3 3.0 -12.0 -10.0 -10.0 SMARTS 3 [#7] SMARTS 3 [#6]
This would tell FRED to create three custom constraint features. The first feature tells FRED a fluorine atom must be within 4.0 Angstroms of (10.0,10.0,10.0). The second feature tells FRED that a carbon double bonded to an oxygen must be withing 5.0 Angstroms of (0.0,0.0,0.0). The third feature tells FRED that a carbon or nitrogen must either be within 3.0 Angstroms of (-10.0,-10.0,-10.0) or within 3.0 Angstroms of (-12.0,-10.0,-10.0).
Every custom constraint feature must have at least one sphere. The distance constraints are always measured from atom center to sphere center. To define a sphere on a residue atom use the ATOM command. It works as follows:
ATOM 1 4.0 150
This command is equivalent to
SPHERE 1 4.0 <x> <y> <z>
Where x,y and z are the coordinates of atom 150 on the target protein.
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