AutoDock requires pre-calculated grid maps, one for each atom type present in the ligand being docked. This helps to make the docking calculations extremely fast. These maps are calculated by AutoGrid. A grid map consists of a three dimensional lattice of regularly spaced points, surrounding (either entirely or partly) and centered on some region of interest of the macromolecule under study. This could be a protein, enzyme, antibody, DNA, RNA or even a polymer or ionic crystal. Typical grid point spacing varies from 0.2Å to 1.0Å, although the default is 0.375Å (roughly a quarter of the length of a carbon-carbon single bond). Each point within the grid map stores the potential energy of a ` probe ' atom or functional group that is due to all the atoms in the macromolecule.
The user must specify an even number of grid points in each dimension, n x , n y and n z . This is because AutoGrid adds a central point, and AutoDock requires an odd number of grid points. The probe's energy at each grid point is determined by the set of parameters supplied for that particular atom type, and is the summation over all atoms of the macromolecule, within a non-bonded cutoff radius, of all pairwise interactions.
The following figure illustrates the main features of a grid map:
The ligand can be seen in the centre of the grid map, buried inside the active site of the protein. In this case, the grid map encompasses the whole protein. The grid spacing is the same in all three dimensions.
As mentioned in the description of the new free energy function, the user can smooth the pairwise potentials, by storing the lowest energy within a given distance of the current pairwise separation. The value of this specified in the GPF, and should not be changed from `
smooth 0.5
' in order to use the function described in the literature
See Morris, G. M., Goodsell, D. S., Halliday, R.S., Huey, R., Hart, W. E., Belew, R. K. and Olson, A. J. (1998), "Automated Docking Using a Lamarckian Genetic Algorithm and and Empirical Binding Free Energy Function", J. Computational Chemistry, 19: 1639-1662.
.
In addition, in
AutoGrid
3.0, the user must use a new utility program to specify the atomic fragmental volume and atomic solvation parameters for each atom in the macromolecule, and for all the carbon atoms in the ligand. This requires the assignment of these parameters to the macromolecule using the program `addsol' to create a PDBQS file. This resembles a PDB formatted file, but in addition gives the partial charges and solvation parameters for each atom. The solvation parameters for the ligand `probe' atoms are specified in the GPF, by the "
sol_par
" keyword, and should not be modified unless the free energy function is not needed.
One last addition to the GPF, is the introduction of a `
constant
' keyword. This was introduced to penalize hydrogen bonds lost upon ligand binding. This defines a constant energy that is added to all the values in a grid map. The rationale for this is as follows: when a ligand goes from the unbound to the bound state, and is capable of making hydrogen bonds, it may or may not lose the enthalpic stabilization of one or more of these H-bonds. We assume that a ligand in the aqueous phase accepts and donates as many hydrogen bonds as it can. However, we found that a plot of the total hydrogen bonding energy for the bound ligand in the protein complex, versus the maximum number of
possible
hydrogen bonds the ligand could form, indicated that on average only 36% of the maximum well depth stabilization was achieved for each
possible
hydrogen bond. Thus a ligand atom in the complex that has a hydrogen bonding capacity must experience at least this amount of stabilization before it can be formed. Those that cannot are penalized by this amount.