What's new?
June 1, 2009

AutoDock 4.2 is faster than earlier versions, and it allows sidechains in
the macromolecule to be flexible. As before, rigid docking is blindingly
fast, and high-quality flexible docking can be done in around a minute.
Up to 40,000 rigid dockings can be done in a day on one cpu.

AutoDock 4.2 now has a free-energy scoring function that is based on a
linear regression analysis, the AMBER force field, and an even larger
set of diverse protein-ligand complexes with known inhibition constants
than we used in AutoDock 3.0. The best model was cross-validated with
a separate set of HIV-1 protease complexes, and confirmed that the
standard error is around 2.5 kcal/mol. This is enough to discriminate
between leads with milli-, micro- and nano-molar inhibition constants.

You can read more about the new features in AutoDock 4.2 and how to use
them in the AutoDock4.2 User Guide.
http://autodock.scripps.edu/faqs-help/manual/autodock-4-2-user-guide/AutoDock4.2_UserGuide.pdf


We have established several methods for users to get support for AutoDock,
including the AutoDock List (ADL) and a new forum for AutoDock users.  
See these and more at http://autodock.scripps.edu


New Features in AutoDock 4.0 (2007)

Flexible Residues in the Macromolecule

AutoDock 4 can now model sidechain flexibility in the macromolecule.

We have added a new keyword to AutoDock 4, flexible_residues or
flexres for short, that you must now use to specify the flexible
residues PDBQT file, if you have sidechain motion in the receptor.
Prior to this change, the assumption was that the input PDBQT file
contained both the ligand atoms and the flexible residues atoms.
Now, a file containing only ligand atoms must be supplied to the
move command, while a second file containing the moving receptor
atoms must be supplied to the flexres command.

AutoDockTools (ADT) has been updated to support the setting up of
flexible receptor sidechains, thanks to the introduction of the new
"Flexible Residues" menu.

ADT now computes the center of rotation of the ligand using only
the ligand atoms. Previously, the center was computed using all the
atoms in the input PDBQT file, which could cause the center to be
far from the ligand atoms when receptor atoms were included in the
ligand PDBQT file; when this was the case, AutoDock was unable to
find a low energy docking.

Unbound Ligand Calculation

AutoDock 4 computes the unbound state of the ligand before docking
as an extended conformation, and includes the difference in internal
interaction energy between this unbound state and the final docked
state, when estimating the free energy of binding. Previously,
AutoDock assumed that the internal energy of the ligand was the
same both before and after binding to the macromolecule.

This is achieved using the compute_unbound_extended command, and
this must be specified after the search parameters have been set,
but before the actual dockings are done (i.e. before ga_run or
simanneal or do_local_only, depending on the type of docking).

Internal Energy Calculations

AutoDock 4 uses a more reasonable distance for the non-bond cutoff
in the internal energy calculations, which speeds up docking compared
to AutoDock 3.

The internal energy calculation now includes the desolvation energy
term. Previously, AutoDock 3 only used the desolvation energy term
in the intermolecular interaction energy.

The internal energy calculation now uses the same distance-dependent
dielectric function that is used in the intermolecular interaction
energy calculation. Previously, AutoDock 3 only used the
distance-dependent dielectric function in the intermolecular
interaction energy.

It is possible to include 1,4-interactions in AutoDock's energy
calculation, and these contributions can be optionally weighted.
This is done using the new include_1_4_interactions command in the
DPF, and may be followed by a scaling factor.

Desolvation Energy Calculations

The desolvation term in AutoDock 4 now supports more atom types
than the Stouten method implemented in AutoDock 3, which is
particularly useful in It now includes the absolute magnitude of
an atom's partial atomic charge to evaluate its contribution to the
total desolvation free energy.

Atom Types

More atom types are supported by both AutoGrid 4 and AutoDock 4.
Specifically, AutoDock 3 supported ligands with a maximum of 6
different atom types, now the limit is 22.

File Formats & Atom Types

Ligands and macromolecules are now stored in the same file format,
namely "PDBQT". The "Q" in "PDBQT" stands for partial charge, and
the "T" stands for atom type.

Atom types are now one or two character strings, and are separate
from the atom name, and are almost always the same as the element
name. The exceptions are hydrogen bond donors and acceptors, and
aromatic carbons. AutoDock 3 used only one character for atom types,
and this was always the first character of the atom name, even when
the first character might have been changed to a lower case letter
(e.g. chlorine atom names had to be modified to have a "c" as their
first character).

AutoDock and AutoGrid version 3 used "PDBQ" format for the ligand,
and "PDBQS" for the macromolecule. The "S" in "PDBQS" stands for
atomic solvation parameter.

In version 4, the solvation parameters are looked up using the atom
type and the supplied parameter library file.

A new command has been added to AutoDock 4, called parameter_file
that expects the name of the AutoDock 4 parameter file. If this
line is omitted, default parameter values are used instead.

The grid parameter file (GPF) and docking parameter file (DPF) are
now shorter and simpler, since the internal non-bond parameters are
now stored in a separate file, the AutoDock 4 parameter file. This
is called "AD4_parameters.dat" by default, but can be called anything.

New Search Algorithms

Coliny is the new search library from Bill Hart, Sandia National
Laboratories. Max Chang, (who, like Bill Hart, is a student of
UCSD's Rik Belew) has been trying out some of the new options in
AutoDock, and contributed this tip. If you want to use any of the
coliny optimisation libraries, you need to create file called
SearchMethod.in in addition to your AutoDock DPF, that lists all
the parameters you want to set for the particular search method,
SearchMethod, you want to use--change the text SearchMethod
accordingly. For instance, a simple real-value-optimizing Evolutionary
Algorithm (EAreal) search would require a file called EAreal.in.
To set the maximum number of energy evaluations to use before
terminating the EAReal search, it would contain the line:

      max_neval 250000

By default, Coliny searches print a lot of debugging information
(detailing the search process) to the standard output, so you may
want to add the line:

    output_level none

To use Coliny in AutoDock, you will also need to add the following
line to your AutoDock 4 DPF, to specify which Coliny search method
and how many docking runs to do:

    coliny EAreal 10

AutoDock 4 Genetic Algorithm (GA) and Lamarckian Genetic Algorithm
(LGA) now support new crossover operators. Previously, AutoDock 3
only offered 2-point crossover. AutoDock 4 now offers the choice
of 1-point crossover, 2-point crossover, uniform crossover and
arithmetic crossover.

Seeding Populations

We have added the ability to "seed" a population when using the GA
or LGA in AutoDock. This means we can specify the particular state
variables for a member of the initial population using the tran0,
quat0 and dihe0 commands in the DPF. This can bias a search, and
if the state variables have come from a previous docking and are
of a good docked conformation (i.e. low energy), then seeding can
dramatically improve the search efficiency of the docking.

