[Dock-fans] Amberscore after MD

[Scott Brozell]

Hi,

On Fri, 15 Aug 2008, Francesco Pietra wrote:

> For a protein and a ligand I carried out rigid docking, flex docking
> and amberscore with DOCK6. Then, the complex protein-ligand was
> embedded in a lipidic membrane for MD simulation with AMBER 10.
> 
> At this point, I would like to carry out amberscore again. Is it wise
> to do that for the lowest_energy_structure captured from MD
> trajectories with ptraj? If so, working out manually the pdb file,
> extracting the parts related to the protein and the ligand for
> "Prepare" with Chimera.
> 
> The alternative (which I tend to disfavor) is the averaged structure
> from the MD simulation.
> 
> Or is anything better?

The simple approach is to use the lowest_energy_structure, because the
averaged structure might not correspond to reality, and to eyeball
any structure as a basic check on reality.

However, more complicated approaches may be better.
In general, one can usually find at least one metric for judging the
quality or appropriateness of the starting structure.
For example, sometimes a particular receptor functional group
interacts with a ligand.  One could form a histogram of the group-to-
ligand distance over the MD trajectory.  The shape of the histogram
would determine the set of starting structures: one big peak - pick
a structure from the peak bin; two separated but similar peaks -
now two starting structures would be necessary; etc.  Other metrics
might be ligand-centric or receptor-centric.

Note that any MD geometry might not be very good, but that might not
matter.  Amber score is probably more sensitive to the geometry
than the other DOCK scores because MM interaction energies are
more forgiving of clashes, etc.
On the other hand, Amber score provides many levels of relaxation
of poor geometries, and using a real Amber MD snaphot would be
already relaxed.  So Amber scoring before and after DOCK docking
might be useful.


On Sat, 16 Aug 2008, Francesco Pietra wrote:

> I forgot to ask about the number of steps for amberscore that may
> hopefully lead to meaningful outputs. After flex docking, I used in
> file
> 
> ligand_atom_file
> /home/francesco/amberscore_everything/flex_scored.amber_score.mol2
> limit_max_ligands                                            no
> skip_molecule                                                no
> read_mol_solvation                                           no
> calculate_rmsd                                               no
> orient_ligand                                                no
> flexible_ligand                                              no
> bump_filter                                                  no
> score_molecules                                              yes
> contact_score_primary                                        no
> contact_score_secondary                                      no
> grid_score_primary                                           no
> grid_score_secondary                                         no
> dock3.5_score_primary                                        no
> dock3.5_score_secondary                                      no
> continuous_score_primary                                     no
> continuous_score_secondary                                   no
> gbsa_zou_score_primary                                       no
> gbsa_zou_score_secondary                                     no
> gbsa_hawkins_score_primary                                   no
> gbsa_hawkins_score_secondary                                 no
> amber_score_primary                                          yes
> amber_score_secondary                                        no
> amber_score_receptor_file_prefix                        protein (with
> all hydrogen atoms in place)
> amber_score_movable_region                                everything
> amber_score_before_md_minimization_cycles                    100
> amber_score_md_steps                                         3000
> amber_score_after_md_minimization_cycles                     100
> amber_score_gb_model                                         5
> amber_score_nonbonded_cutoff                                 18.0
> amber_score_temperature                                      300.0
> ligand_outfile_prefix                                        output
> write_orientations                                           no
> num_scored_conformers_written                                1
> rank_ligands                                                 no
> 
> In order to re-run amberscore after MD in the membrane, how many
> (minimum) steps may be suggested?
 
That is an open question.  My feeling is that your receptor preparation
is extremely good compared to the typical for docking.  So the above
protocol may be ok.  As usual, to guage the protocol will require more
calculations: systematically increase the cycles, steps, and movable sizes
and look for convergence.
http://blur.compbio.ucsf.edu/pipermail/dock-fans/2007-April/001010.html

Scott