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The MakeGrids tab

1) Tab description:

The MakeGrids tab is central to making advanced docking strategies because, from this tab, users can: (a) include or exclude the flexibility of the receptors in the calculations; and (b) search for the ligand-binding site in all the receptor surface ("Area around the whole receptor surface " option) or in a user-defined portion of it ("Area around one specific point" option) using, in both cases, a grid-point distance as short as they like regardless of the dimensions of the three-dimensional space that is searched. Users can then combine the flexibility and ligand-binding site location strategies according to their needs (e.g. they can do the docking in a specific part of a flexible receptor). For each protein, this tab can automatically deal either with a single PDB file or with a set of PDB files corresponding to different snapshots of its conformations [such as those that can be readily obtained from FlexWeb tools (Zavodszky et al., 2004) or retrieved from the MODEL database]. Here the user does not need to do anything special to take into account receptor flexibility. Receptor flexibility is automatically assumed for those receptors provided to this tab by the user's list that have more than one PDBQS file (where PDBQS corresponds to the input format for the receptors in AutoGrid) in the selected PDBQS directory [it is assumed that PDBQS filenames that start with the same four-character code (usually a PDB code) correspond to different conformations of the same receptor].

This tab is used to control where AutoGrid has to run (i.e. around one specific point or around all the receptor), define the number of grid points per dimension (i.e. the dimensions of what we call a "partial box"; see below), establish the minimum separation between two grid points in the lattice, and set the "security distance" (though this is only used when the "Area around the whole receptor surface" option is activated). The "security distance" is used to increase the length, in the three dimensions, of the smallest box that is able to contain all the receptor's atoms (thus ensuring that the ligand will have enough room to "walk" around all the receptor surface and find the preferred sites for binding; see below in the algorithm description).



If the user selects the "Area around one specific point" option, a new window appears with the list of receptor's PDB codes and for each one the user must indicate: (a) the coordinates of the central point of the receptor's area of interest, and (b) the number of partial boxes that will be used in each dimension.



The rest of the running conditions are read from a gpf file that is used as a model to build all the gpf files that are needed for the AutoGrid runs that follow after the "execute" button is pressed. We provide BDT users with a couple of gpf files that can be used as models [one for proteins without cofactors (i.e. the model_gpf_basic file that can be used as a default selection) and one for proteins with Fe as cofactor (i.e. the model_gpf_withFe file)], but users can easily build new ones with AutoDockTools (ADT) according to their specific running and receptor needs. This couple of gpf file templates are in the library directory of the original BDT distribution.

If "Quantity of information sent" is set to 5, then make_grids (the Fortran program under this tab) can e-mail a PDB file to the users every time make_grids stops working with one receptor or with one conformation of the current receptor (if receptor flexibility is used). This file is not intended for analyzing results but can be used as a record for future reference because it contains: (a) the coordinates of the self receptor; (b) a box showing the location of the receptor's area of interest; and (c) the different "partial boxes" inside this area. This PDB file can be easily handled (e.g. coloured, hidden, etc.) by molecular graphic programs such as RasMol (Sayle and Milner-White, 1995) because coordinates from the receptor, from its area of interest or from the partial boxes contained in this area are labelled as belonging to different subunits ("R" for the receptor, "T" for the area of interest and "P" for the partial boxes).



2) Algorithm description for make_grids:

1) make_grids takes the input information provided by the MakeGrids tab
2) make_grids takes the first receptor in the list and calculates the dimensions of the smallest box (the so-called "minimum box"; see green box in the above Figure) that is able to contain all the atoms of its different conformations [where the different conformations for the same receptor are automatically recognized by make_grids because their filenames share the first four characters (that usually corresponds to a PDB code)].
3) make_grids adds to each "minimum box" dimension the value that corresponds to the "security distance" and obtains the so-called "total box" (see the blue box in the above Figure).
4) If the "total box" does not contain an integer number of "partial boxes" (i.e. the area that will be used by each AutoGrid's run), the corresponding dimensions of the "total box" are conveniently increased in size until it does.
5) make_grids divides the "total box" into "partial boxes" (see the yellow boxes in the above Figure) and runs an AutoGrid process inside each one. Now, the "total box" corresponds to the receptor's area of interest.
6) AutoGrid output files for each "partial box" are conveniently labelled and stored for further use by combine_grids (if more than one conformation is available for the receptor) or directly by make_docks
7) After running AutoGrid inside all the "partial boxes" of a specific receptor, make_grids repeats either step 6 with the next receptor conformation or from step 2 to 6 with the next receptor in the list.

The above algorithm follows one slightly different pathway if the "Area around one specific point" option is used because, in that case, no "minimum" and "total" boxes are calculated by make_grids and the number of "partial boxes" used by the program correspond to those that have been indicated by the user. The next Figure shows the result of running make_grids around a selected point (indicated by the red ball):