Types of Docking (Induced fit, Rigid receptor, etc)

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If the bond angles, bond lengths and torsion angles of the components are not modified at any stage of complex generation, it is known as rigid body docking. A subject of speculation is whether or not rigid-body docking is sufficiently good for most docking.

For this model the protein/receptor is the “lock” and the ligand/lead is the “key”. Both the internal geometry of the receptor and the ligand are kept fixed during docking. One then finds the correct relative orientation of the “key” which will open up the “lock”.

In the rigid molecule docking problem we will relate to the molecules as rigid objects that cannot change their spatial shape during the docking process. In molecular biology, there are two main problems where the docking problem arises: The ligand-protein docking and the protein-protein docking problems.

In this first case, the ligand will be kept completely rigid during the orientation step. The purpose is to explore the matching and minimization algorithms. However, this type of docking could be applied in a scientific setting if we have a library of ligands that have already been conformationally expanded outside of the DOCK suite of programs.

Conceptually, the algorithm matching the centers of the ligand heavy atom to the centers of the receptor site spheres. The algorithm follows the steps below:

  • Generate node

  • Label as match if atom and sphere edges are equivalent

  • Extend match by adding more nodes

  • Exhaustively generate set of non-degenerate matches

  • Use matches to create transformation matrices to move the entire molecule

Once an orientation has been generated, the interaction between the ligand and the receptor can be energetically optimized, in this case using a simplex minimizer. During minimization, the ligand is allowed to be flexible, but the receptor remains rigid. The final score in the output file is the best pose generated from the orienting and minimization procedure.

Induced fit/Flexible Ligand Docking

In this type, the ligand will be allowed to be flexible. This type of docking allows the ligand to structurally rearrange in response to the receptor.

First, the largest rigid substructure of the ligand (the anchor) is identified. All bonds within molecular rings are treated as rigid. This classification scheme is a first-order approximation of molecular flexibility, since some amount of flexibility can exist in non-aromatic rings. To treat such phenomena as sugar puckering and chair-boat hexane conformations, the user needs to supply each ring conformation as a separate input molecule. If the molecule does not have a ring, the largest rigid segment is specified as the anchor. Additional bonds may be specified as rigid by the user.

Next the flexible layers of the ligand are identified. Each flexible bond is associated with a label defined in an editable file. The parameter file is identified with the flex_definition_file parameter. Each label in the file contains a definition based on the atom types and chemical environment of the bonded atoms. Typically, bonds with some degree of double bond character are excluded from minimization so that planarity is preserved. Each label is also associated with a set of preferred torsion positions. The location of each flexible bond is used to partition the molecule into rigid segments. A segment is the largest local set of atoms that contains only non-flexible bonds.

In the second stage of the Anchor-and-Grow Algorithm the anchor is rigidly oriented in the active site using the same method. The anchor orientations are evaluated and optimized using the scoring function and the simplex minimizer. The orientations are then ranked according to their score, spatially clustered by heavy atom root mean squared deviation (RMSD), and prioritized (pruning).

Finally, in the growth stage the flexible layers of the ligand are built onto the best anchor orientations within the context of the receptor. It is assumed that the shape of the binding site will help restrict the sampling of ligand conformations to those that are most relevant for the receptor geometry.

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