Creating a Receptor¶
The protein structure should only include molecules the ligand is expected to interact with. In general crystallographic waters, other solvents and the bound ligand should be not be included as part of the target protein structure passed to the OEMakeReceptor function, although in certain cases, the user may wish to retain certain key molecules as part of the target protein structure (e.g. a crystallographic water).
Contents of a Receptor¶
The negative image describes the shape of the active site. It is stored as a potential grid surrounding the active site. Potential values are always greater than or equal to zero. The negative image has high potentials where ligand atoms make many contacts with atoms of the active site without clashing and in positions some ligand atoms are likely to occupy when other atoms of the ligand make good contacts with the receptor (e.g. bridging positions ligand atoms will likely occupy when a ligand is stretched between two pockets).
During docking two shapes are created by contouring the negative image potential grid. The two shapes control the docking process as follows:
Outer Contour Shape
During docking any pose examined by the exhaustive search that does not fit within this shape will be rejected. A pose is considered to fit if the center of every heavy atom is within this shape. The volume of this shape is typically between 500 and 2000 cubic Angstroms.
Inner Contour Shape
During docking any pose examined by the exhaustive search that does not touch this shape is rejected. A pose is considered to touch if the center of at least one heavy atom falls within this shape. The volume of this shape is typically 50 to 100 cubic angstroms.
While neither the outer contour nor the inner contour shape are required, it is recommended that the outer contour always be used (docking speed will be dramatically slower without the outer contour). Using the inner contour improves docking speed slightly at the expense of sampling.
The negative image of the receptor is setup when the receptor is created with the OEMakeReceptor function (see Creating a Receptor section). The size of the outer contour and inner contour shapes are controllable by setting the contour level used to create the shape from the negative image. The OEMakeReceptor function will automatically set a reasonable contour level for both the inner contour and outer contour, however the inner contour will be disabled by setting the value to be negative (see below).
The negative image grid has only positive values, thus only contour levels that are positive create a shape. When either the outer contour level or inner contour level are negative that contour shape will be disabled (i.e. ignored during the docking process).
The volume of the outer contour shape has a significant effect on docking speed, while the volume of the inner contour shape has a modest effect on docking speed. In both cases the smaller volumes increase docking speed by reducing the number of poses that are scored. In general an outer and inner contour volume of between 500-2000 and 50-100 cubic Angstroms respectively is recommended.
Constraints are key interactions ligands are required to make when docking into the active site. They are optional and user defined.
Constraints do not affect how a given pose scores, however they do affect how the docking algorithm chooses poses to score during the docking process. Any pose that does not match the docking constraints will be rejected and replaced by the next best scoring pose. If no poses of a ligand match the docking constraints the ligand will not be docked. If multiple constraints are specified every constraint must be satisfied or the pose will be rejected.
The docking process has a resolution of approximately 1 Ångström, and thus the constrains have a similar resolution. Therefore it is possible that poses docked with a constraint may have small violations of the constraint distance, up to approximately 1 Ångström.
Receptors support two general classes of constraints; protein constraints and custom constraints. There may be any number of either class of constraint.
Each individual custom or protein constraint has an enabled flag. A disabled constraint is ignored during the docking process.
A protein constraint specifies an interaction that must be made with a heavy atom of the protein structure (i.e. protein constraints cannot be placed on hydrogen atoms). There are five types of protein constraints.
A contact constraint is satisfied when any ligand heavy atom is within 4 angstroms of the protein heavy atom.
A lipophilic constraint is satisfied when any non-polar heavy atom on the ligand is within 4 angstroms of the protein heavy atom.
A donor constraint is satisfied when a donor on the ligand makes a hydrogen bond interaction with the protein heavy atom.
An acceptor constraint is satisfied when an acceptor on the ligand makes a hydrogen bond interaction with the protein heavy atom. Acceptor constraints must be placed on the protein heavy atom the donor hydrogen is interacting with.
A chelator constraint is satisfied when a chelator on the ligand makes a metal-chelator interaction with the protein heavy atom.
Only one protein constraint is allowed per protein heavy atom. If a protein constraint is set on a protein atom that already has a protein constraint the original protein constraint will be discarded and replaced by the new constraint.
A custom constraint consists of one or more spheres within the receptor active site, and optionally a list of SMARTS patterns. A custom constraint is satisfied when a matching atom on the ligand falls within any of the spheres associated with the custom constraint. If no SMARTS patterns are specified any heavy atom on the ligand can satisfy the constraint, otherwise only atoms that match one of the smarts patterns can satisfy the constraint.