On Thu, Feb 28, 2013 at 1:00 PM, Vivek Shankar Bharadwaj <
vbharadw.mymail.mines.edu> wrote:
> 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?
>
You really should have all bug fixes applied -- they all fix bugs ;). The
one in particular that I'm talking about is bugfix.27 (
http://ambermd.org/bugfixesat.html). If you don't have all bug fixes
applied, make sure you update and re-compile.
>
> 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?
>
Look at how the energies are decomposed -- what is the biggest contributor
to destabilizing the binding (not on a per-residue basis, but on an energy
term basis, like ENPOLAR, EEL, VDW, etc.). This is a good first place to
look.
>
> 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?
>
No. This has been discussed numerous times in the past on this list. The
key issue here is double-counting.
>
> *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?
>
That could also help, especially if you are struggling to make sense of
your decomp results.
HTH,
Jason
--
Jason M. Swails
Quantum Theory Project,
University of Florida
Ph.D. Candidate
352-392-4032
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Received on Thu Feb 28 2013 - 10:30:04 PST
