Hi Jason and Aron,
Thanks a lot for your insights. I think I still have a few more questions,
*Have you applied all bug fixes to AmberTools 12? You can check if more
patches are available by doing:
**cd $AMBERHOME && ./patch_amber.py --check-updates**
There was a bugfix not too long ago that was a pretty substantial fix to
the PB part of MMPBSA.py.
**As for why binding free energies could be positive for PBSA and negative**
for GBSA, that would depend on your system. The decomposition analysis may
be able to help with that.
*
1. I checked for the updates, and the update relating to the PSBA
calculations has been applied.
However, I found that one of the updates (bug14) enables GBSA calculations
on the GPU. Is this applicable to MMGBSA calculations also?
2. How do you think the decomposition analysis may help to understand PBSA
binding energies? I did notice that the PBSA and GBSA decomposition
energies were strikingly similar (on a per residue basis) although the
total Binding energies are significantly different.
Can I assume that the unfavourability is due to some other reasons and not
due to the unfavouability of the ligand-enzyme interactions at the active
site?
3. Do the total decomposed energies (sum for all the residues) have to be
equal or almost equal to the total MMGB/PBSA binding energies?
*It sounds like solvation effects -- you're effectively measuring the*
*difference between solvating a hydrophobic compound in a protein vs water.
Virtually all ligand-receptor interactions for toluene will be weak, since
the charges on toluene should be pretty small, and vdW interactions are
short-ranged and typically pretty weak. The surface area effects here I
would expect to be pretty large, and that is a difficult value to
'decompose'.*
*
*
I think I now understand why the ligand contribution for Toluene is so high.
4. Would you suggest that alanine scanning to be a better alternative (as
compared to decomposition analysis) for quantifying the contribution of a
specific residue to ligand binding?
On Wed, Feb 27, 2013 at 6:53 PM, Jason Swails <jason.swails.gmail.com>wrote:
> On Wed, Feb 27, 2013 at 7:28 PM, Vivek Shankar Bharadwaj <
> vbharadw.mymail.mines.edu> wrote:
>
> > Hi AMBER Users,
> >
> > I am new to MMPB/GBSA calculations and am studying the binding of
> toluene,
> > fumaric Acid and benzylsuccinate to an enzyme. I was able to get the
> > implementation to work successfully for my system. I have some questions
> > regarding the analysis.
> >
> > I have been able to calculate the overall binding energies using MMGBSA,
> > MMPBSA and decompose the binding energies among the key residues at the
> > active site.
> >
> > I have the following questions with regards to analyzing the results
> >
> > 1. I find that the total binding free energies calculated from MMGBSA
> give
> > negative free energies of binding while the MMPBSA binding energies are
> > positive (~1 kcal/mol). Why would the MMPBSA free energies show
> > unfavourable binding while MMGBSA show favourable? The MMGBSA and MMPBSA
> > energies also do not display the same trend for my ligands.
> >
>
> Have you applied all bug fixes to AmberTools 12? You can check if more
> patches are available by doing:
>
> cd $AMBERHOME && ./patch_amber.py --check-updates
>
> There was a bugfix not too long ago that was a pretty substantial fix to
> the PB part of MMPBSA.py.
>
> As for why binding free energies could be positive for PBSA and negative
> for GBSA, that would depend on your system. The decomposition analysis may
> be able to help with that.
>
>
> > 2. I understand that the ligand also has to be mentioned in the print_res
> > specification for decomposition. In the output, (delta's total energy
> > section) the ligand contribution to the binding energy is also reported.
> I
> > am finding it difficult to understand how the ligand's binding energy be
> > decomposed onto itself?
> >
>
> You are not decomposing the binding free energy. You are decomposing the
> energy itself. Atoms with the ligand interact with each other. Therefore,
> there is a "self" interaction between ligand residues.
>
> Furthermore, PB and GB are not pairwise decomposable, since the dielectric
> boundary for PB and the effective GB radii for GB are dependent on all of
> the surroundings. Therefore, intra-ligand interactions will not
> necessarily be the same in the bound and free states. All pairwise terms
> should cancel (e.g., VDW, 1-4 VDW, 1-4 EEL, EEL, internal), but the
> solvation terms --specifically ESURF/EGB or ECAVITY/EPB--will differ (that
> would be sas and pol in the decomp language).
>
> 3. I find that the majority (~90%) of the binding energy (deltas of the
> > total energies in the output) for the toluene binding is attributed to
> the
> > ligand itself. [Meaning that the B.E remains undecomposed]. What could I
> be
> > doing wrong? or is this due to the hydrophobic interactions stabilizing
> > toluene? In the case of fumaric acid the ligand contribution was ~20%
> only.
> >
>
> It sounds like solvation effects -- you're effectively measuring the
> difference between solvating a hydrophobic compound in a protein vs water.
> Virtually all ligand-receptor interactions for toluene will be weak, since
> the charges on toluene should be pretty small, and vdW interactions are
> short-ranged and typically pretty weak. The surface area effects here I
> would expect to be pretty large, and that is a difficult value to
> 'decompose'.
>
> HTH,
> Jason
>
> --
> Jason M. Swails
> Quantum Theory Project,
> University of Florida
> Ph.D. Candidate
> 352-392-4032
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>
--
Vivek S. Bharadwaj
Graduate Student
Department of Chemical and Biological Engg.
Colorado School of Mines
Golden Colorado
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Received on Thu Feb 28 2013 - 10:30:03 PST
