As already described in the Introduction, AutoDock can use Monte Carlo simulated annealing (SA), a genetic algorithm (GA), a hybrid genetic algorithm-local search (LGA), an evolutionary programming (EP) or a pure local search (SW or pSW) engine in order to explore the conformational states of a flexible ligand.
Quaternion rotations 1 have been implemented in handling the rigid body orientation of the ligand. It was found that this gave finer control over the movement of the ligand, and gave better docked solutions than with the alternative Eulerian rotations. Quaternions also avoid the gimbal lock problem that Eulerian angles suffer from.
A docking "job" is a single AutoDock process, which carries out a number of independent docking "runs", each of which begins with the same initial conditions. A simnulated annealing (SA) run is a sequence of constant temperature annealing cycles. A genetic algorithm (GA, LGA or EP) run consists of a series of generations. Each job can be seeded with a user-defined or a time-dependent random-number generator seed. If time-dependent seeds are requested, this value is updated each time a run starts, so 10 runs in one job get 10 different seed values.
The various parameters for the docking are usually stored in a docking parameter file, or "DPF". This is passed to AutoDock using a command line flag (-p). These flags will be discussed in greater detail later on. It is advisable to do a short run to check the DPF, before committing to spending billions of computer cycles. If there is any problem, a short run should find it.
Whatever search engine is chosen, the DPF must define the following: the random number generator seed or seeds using "
seed
"; the atom "
types
" in the ligand, that match the grid maps produced by
AutoGrid
; the "
fld
" field file that describes the spatial extents of the grids; and the names of the "
map
" files themselves.
AutoDock
must be told what filename contains the ligand to "
move
", and "
about
" which x,y,z coordinate the rotations and translations will be centered. The x,y,z values used in the "
about
" command must be in the same coordinate frame as the coordinates in the ligand PDBQ file specified in the "
move
" command.
Currently in AutoDock 3.0 , the intial state of the ligand can only be set using SA. All evolutionary search methods, GA, LGA and EP, automatically start with a random population. It is not possible to seed a population with user-defined individuals in version 3.0
The initial translation and quaternion of this ligand may be set in SA dockings only, using the "
tran0
" and "
quat0
" keywords.
The step sizes for making changes to the state variables affect SA
and
the evolutionary methods, GA, LGA and EP. They are defined using the "
tstep
", "
qstep
" and "
dstep
" keywords. The default values are: translation, 0.2 Å, rigid-body orientation and dihedral angles, 5°.
If the ligand is conformationally flexible, the user may specify, for SA only, the number and initial values of the initial dihedral angles using "
ndihe
" and "
dihe0
". If the keyword "random" is given instead of explicit values, the ligand starts the SA with a random conformation.
The internal non-bonded potential parameters are defiend using the "
intnbp_coeffs
" or "
intnbp_r_eps
" keywords. The former accepts coefficients while the latter accepts equilibrium separations in angstroms and well depths in kcal/mol. The latter input method is more intuitive.
The user should specify the level of output during dockings, using "
outlev
". Essentially, the higher this integer, the more output is generated. A value of 1 is normally used.
If the user gives the "
analysis
" command, then after all the docking runs are completed in a given job, cluster analysis or `structure binning' will be performed. This is based on positional root mean square deviation of corresponding atoms, ranking the resulting families of docked conformations in order of increasing energy. AutoDock writes out a histogram showing the number of conformations in each cluster, and represents it `graphically' using a bar chart of `
#
' symbols. Search the AutoDock log file for the phrase `
HISTOGRAM
' all in upper-case, and you will see the cluster analysis results.
The default method for structure binning allows for symmetry rotations. For example, a tertiary butyl can be rotated by +/-120° and it will be chemically equivalent to the original conformation. In other cases it may be desirable to bypass this similar atom type checking and calculate the rms on a one-for-one basis: this can be done using the "
rmsnosym
" keyword. When clustering the conformations, the root mean square deviation tolerance "
rmstol
" and reference structure "
rmsref
" filename should be specified. Typical values for
rmstol
range from 0.5 to 1.5 Å.
AutoDock's analysis tool compares all the docked conformations with one-another, and if two conformations have an rmsd that is less than the rmstol value, they are both stored in the same cluster. This is repeated for all conformations, and the clusters are output ranked in order of increasing energy from most negative to most positive. To perform the cluster analysis, the keyword "analysis" must be given after the dockings have finished, on the last line of the DPF. It uses the `
rmstol
', `
rmsref
' and `
rmsnosym
' commands set earlier in the DPF.
The next sections describe the parameters specific to the different search engines.