[Dock-fans] amber_score

Francesco Pietra chiendarret at yahoo.com
Fri Nov 2 00:31:52 PDT 2007

Thanks indeed for comments and guidelines. As to amber_score, please see my
answer at penultimate paragraph.

--- Scott Brozell <sbrozell at scripps.edu> wrote:

> Hi,
> I answered some of these in the latest 'Combining DOCK with AMBER'
> but reproduce them for simplicity.
> On Wed, 31 Oct 2007, Francesco Pietra wrote:
> > I open a new thread (amber_score) because previous thread (Combining Dock
> with
> > Amber) was becoming too complex, in the hope to get some general
> guidelines.
> > 
> > To summarize
> > 
> > (1) With a pore protein model and a flexible 150-atoms ligand (working with
> > Dock6.1 and Chimera 17 Oct build) I could carry out both rigid_docking and
> > flex_docking along the default lines of the tutorials. The ligand is seen
> > inside the pore, roughly the same view in both cases.
> Good.
> > (2) As prepared with Chimera, the protein did not allow to get (via
> dock-prep)
> > the prmtop and inpcrd files needed for amber_score. Therefore, I prepared
> the
> > protein with Leap in Amber9, getting prmtop and inpcrd, which allowed a
> correct
> > graphical representation in both Chimera and VMD.
> This is not surprising since Amber's LEaP (which is the vehicle for
> amberization under the hood of DOCK's prepare_amber.pl)
> is the sole mechanism for Amber input preparation.
> Here is the usual sequence:
> Do docking (along the lines of tutorials
> Structure Preparation,
> Sphere Generation and Selection,
> Grid Generation,
> Docking );
> Then rescore with Amber_score (along the lines of tutorial
> Structure Preparation & AMBER Score ).
> Note that Amber_score has receptor input files distinct
> from DOCKing receptor input files.
> Typically, one has an original pdb which is the starting point for
> dock prep, and the resulting mol2 file (from step 2f in the
> Structure Preparation tutorial) also can be saved as a pdb;
> it is this later pdb that is usually the starting point for
> prepare_amber.  However, one can imagine several ways to
> obtain the actual receptor input files; for example, one might
> take the pdb file from step 2g and use that for prepare_amber.
> This would be a simple consistency test for protonation
> between the DOCKing receptor and the Amber_score receptor.
> It seems to me that you are performing various consistency checks
> between DOCKing inputs and Amber_score inputs.
> That is a sound approach, but human inspection will play a
> dominant role since the DOCK and the Amber packages are
> not input compatible (despite the appearance through the
> magic of amberization).
> [Note to Amber/DOCK superexperts: there are several caveats
> that I have ignored for pedagogical purposes.]
> > (3) The pdb file for the protein created in Amber9 from prmtop and inpcrd
> with
> > ambpdb proved unsuitable for Chimera dock-prep (standard amino acids were
> > mis-viewed as non-standard residues and assigned to Antechamber, which
> wrongly
> > calculated fractional charge for the residues). I changed strategy, loading
> the
> > protein to Chimera from the Leap-created prmtop and inpcrd files. That also
> > failed (dock-prep), but for a different reason, Value Error: underlying C++
> > Molecule object is missing (I have documented that with an error.log on
> > previous thread), which I do not understand.
> Please post this small episode to Chimera-users.
> This may be an issue of operator error, but maybe not and
> anyways it may help them improve robustness.
> > Now the files from Leap (2 above) allowed amber_scoring. I carried out both
> a
> > rapid (few minutes) "ligand" option and a longer (4 hours) "everything"
> option.
> > In both cases, from the complex "final_pose.amber.pdb", the ligand is
> immersed
> > into the protein, though not along the pore walls, unlike with the rigid
> and
> > flex docking mentioned in (1). The bad point is that the ligand was broken
> into
> > two major fragments, and minor CH2 fragments. At a rough inspection, the
> > protein does not appear to have suffered any major damage, in both options.
> I
> > must add that breakage of the ligand is surprising because it is a
> thermally
> > very stable molecule.
> Something is amiss - covalent bonds should not break.
> Did you run prepare_amber.pl ?

Yes, I did. The procedure is reported to allow checking if there were opetator
mistakes before running prepare_amber.pl:

(1) After several adjustments (HID in place of HIS, GLH in place of GLU and
swap of oxygen names and rename H, etc., the protein was fed to Leap in Amber 9
(leaprc.ff99SB), whereby missing heavy atoms were added where I had placed TER
records, and "38 H / lone pairs" were also added. I could save prmtop and
inpcrd, being advised that there are 4 separate chains with N and C termini.

(2) From these prmtop and inpcrd  I got the rec.pdb file using ambpdb program.

(3) I run 

prepare_amber.pl lig.mpl2 rec.pdb

where lig.mol2 had been obtained along tutorial-like dock procedures.

The rec.lig.1.final_pose.amber.pdb was defective as to the ligand as reported
above. Messing of coordinate ligand must have occurred. Values must be wrong,
otherwise the section for the ligand is correctly ordered at the end of the pdb
file, separated by "TER" from the standard residues and ending with "TER".

I checked that


showed the structure of the ligand intact.

All that occurred with either "ligand" or "everything" option in dock.in, which
was otherwise like on amber_score tutorial.

Either I did some operator mistake, or there may be problems with large ligands
in amber_score.



> > I am much confused about the line to follow for amber_score. As carried out
> > above, the receptor has no spheres, while the ligand mol2 file was taken
> from
> > the tutorial-like procedures. Does the receptor pass through the stages of
> > spheres/grid also for amber_score?
> Amber_score only uses a sphere representation of the receptor
> for the distance-movable-region.  Otherwise Amber_score does not use
> any spheres, and it never uses any grids.
> Perhaps my comments to (2) are useful here ?
> Scott

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