In version 3.0 of AutoGrid and AutoDock , we introduced a new kind of scoring function that is used during and at the end of the dockings. It is based on the principles of QSAR (quantitative structure-activity relationships) and was parameterized using a large number of protein-inhibitor complexes for which both their structure and inhibition constants, or K i , were known. The user is encouraged to refer to the description of how this free energy function was derived in the original 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. .
The key point to bear in mind is that parts of the new scoring function are essentially the same as the original scoring function used in versions prior to 3.0, except that various terms in the molecular mechanics energy function have been re-scaled by new coefficients, and new terms have been introduced. These new terms include the desolvation free energy of the ligand, and an estimate of the loss of conformational degrees of freedom of the ligand upon binding.
The coefficients were arrived at using linear regression analysis, and we chose the linear regression model that most closely fit the observed inhibition constants. Thus the user should not modify these coefficients lightly.
For the curious, these coefficients are defined in "gpf3gen.awk" and "dpf3gen.awk", and their variable names and values are as follows:
#
# Free energy model 140n coefficients:
#
FE_vdW_coeff = 0.1485
FE_estat_coeff = 0.1146
FE_hbond_coeff = 0.0656
FE_tors_coeff = 0.3113
FE_desol_coeff = 0.1711
So for example, in See Self-consistent Lennard-Jones 12-6 parameters. and See Self-consistent Hydrogen bonding 12-10 parameters. , the values used in the AutoDock 3.0 scoring function will be as given except the van der Waals coefficients and well depth energies, e, will be scaled by 0.1485, the electrostatic energy will be scaled by 0.1146, and the hydrogen bonding coefficients and well depth energies, e, will be scaled by 0.0656. The new terms for loss of torsional degrees of freedom upon binding and the ligand desolvation free energy will be scaled by 0.3113 and 0.1711 respectively.
Note that the new desolvation free energy term is only calculated for aliphatic and aromatic carbon atoms in the ligand. We found that the quality of the final empirical free energy model was not affected by the inclusion of the heteroatoms N and O in this term, so these are ignored for simplicity and speed of calculation. This does mean that the ligand input PDBQ file must distinguish between carbon atoms that are aliphatic and those that are aromatic. This is done by changing the atom names of the aromatic carbons so that the initial `C' is replaced by `A'. For example, if the ligand happened to be a peptidomimetic inhibitor which contained a Phe-sidechain, then the atom names in the PDBQ file would have to be changed from CG, CD1, CD2, CE1, CE2 and CZ, into AG, AD1, AD2, AE1, AE2 and AZ, respectively. To help the user do this automatically, AutoTors has a new option that can be invoked using the `-A' flag on the command line. This will look for all planar cyclic carbons and assume these are aromatic: it will then change their atom names automatically. The user can also override the default angle AutoTors uses to determine planarity. See the Section below on AutoTors .
This also means AutoGrid will calculate two different types of carbon grid maps, one for aliphatic carbons in the ligand (*.C.map), and one for aromatic carbons in the ligand (*.A.map). These will be input by AutoDock for the docking calculations, and the internal energy parameters must also specify the values for the aromatic and aliphatic carbon atoms.