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Docking

Docking with Moloc

General remarks

Moloc has a docking utility which can be accessed interactively (lib/c) or in batch mode (program Mdck).
For efficient performance the user has to prepare a 'force' entry beforehand which serves to preselect the conformations that fit best into the cavity.
Force entries consist of force agons which are displayed as sphere sections, represented as a sets of rings, each. If switched 'active' they exert a force on atoms in dynamics runs with the force field MAB (Their force cannot be derived from a potential, whence they do not affect force-field minimization runs). The forces are directed along the axes indicated by the centers of the rings and point away from the sphere centers (imagine bumpers of railway cars). However, these forces are only experienced by atoms within the volume of the spheres of the agons.
Force entries are stored in .php file format, and their agons can be modified in the pharmacophore menu 'php' (position, direction and sphere radius).
In the context of docking, force entries are used to push ligand molecules in proper position and modify their torsional angles to optimally adapt to the shape of the cavity. They have no pharmacophore properties by themselves and completely ignore the ones of the ligands.
In addition, a final optimization step with the force field can be applied, which optimizes and evaluates all detailed intermolecular interaction. During this step the cavity atoms can optionally and selectively also move under force field action (induced fit mode).

Preparing a Positions Entry

During a docking run molecules are initially positioned with their centroids at the positions given by a positions entry. If no such entry is given, the centroids of the molecules as given initially are taken as starting positions. An example file 4dfr_B_ps.php can be found in the moloc/dat directory.

Preparing a Force Entry (optional)

An example file 4dfr_B_frc.php can be found in the moloc/dat directory.

Interactive Docking

Now we have all ingredients for a docking run: force entry '4dfr_B_frc', positions entry '4dfr_B_frc', and cavity (environment) entry '4dfr_B_env', as well as a molecule, trimethoprim, to dock. Now the program docks tripethoprim into the cavity of DHFR. The steps of this process can be described by interpreting the generated output:

trimethoprim
Parameters initialized for STANDARD force field! 1(2,2,1,1,1) 2 symmetries
672 cases: t 4(4), o 84, p 2
Max. extension 7.59
672 raw conformations
00000,46,2: -3.398e+001 -> -4.607e+001
01000,9,2: -2.790e+001 -> -3.874e+001
...
12 minimized
1 keep: 01000,35,2 -7.356e+001

The line after the molecular name characterizes the 5 torsional bonds and the number of initial values for each (in brackets).
The next line gives the number of initial conformations (672), the product of number of rotamers (4), orientations (84), and positions (2). After processing by the force minimizer, which adjusts position, orientation and torsional angles, the 672 raw conformations are juged by a coarse force field evaluation (see below) and ranked correspondingly. The top (12) cases are subjected to detailed minimization by the MAB force field. The corresponding lines show the numbers of torsional bond settings, of the orientation and of the position, then after the colon the coarse energy and finally the result of minimization. A second ranking takes place and the top structures (1) are kept in memory.

Batch Run Docking with Program Mdck

The batch programm Mdck expects the ligands in mol format (.sd). Furthermore, the input .sd file must not contain explicit hydrogens nor multi-fragment entries! Use Mol3d to prepare the input file.

Coarse Force Field Energy Estimate

For the ranking of initial poses only non-bonded intermolecular interactions are considered. All intramolecular terms of the ligand are omitted at that stage. Two types of terms are evaluated: