Dear Aron,
in the realm of MM-PBSA, we have used two different ways of decomposing the (vibrational) entropy contributions for what you describe below.
I. Following an idea of S. Fischer et al., "to estimate the entropic contributions a single residue (side-chain) adds to the binding free energy, calculations of translational, rotational, and vibrational entropies are repeated with vanishing masses of the atoms belonging to the residue (side-chain) of interest.
The difference between these entropy values and those obtained with normal masses
then yields the intrinsic contribution of the residue to the entropy of binding." (see Gohlke, Kiel, Case, J Mol Biol 2003). Here, you would need to generate (hand-edited) prmtop files with masses of the appropriate atoms set to zero and repeat the entropy calculations for each residue of interest separately.
II. We have applied a per-residue structural decomposition of the vibrational entropy as introduced by Zoete and Michielin in a recent study on the influence of the solvent representation on vibrational entropy calculations (see Kopitz, Cashman, ..., Gohlke, J Comput Chem 2012). This method gives you the contributions of all residue "in one sweep". Note, however, that while the total entropy is a state function
(and, as such, is independent of the pathway used to calculate it), entropy components, in general, are not. This method is available in the mm_pbsa.pl version of Amber12.
Best regards
Holger
On 16.02.13, Aron Broom
wrote:
> Hi AMBER users,
>
> I'm wondering if it is theoretically possible to decompose the entropy term
> from an MM PBSA/GBSA calculation to determine the contribution of each
> residue?
>
> I realize the script currently does not support this, and the manual makes
> that quite clear. I also believe I understand that in taking in the whole
> complex there would be no way to actually do this decomposition easily.
> What I'm wondering is, from a theoretical perspective, if one did the
> normal alignment of the whole complex to remove those irrelevant rotations
> and translations, and then stripped out all but the residue of interest,
> and performed the entropy calculations (Quasi-harmonic or nmode) on just
> that reduced trajectory (which has been pre-aligned as part of the whole
> complex), would you get something sensible? That is, would doing this for
> each residue give a final result that more or less added up to what you
> would get from doing the whole complex (I realize there is a lot of
> uncertainty in entropy calculations as it is, and so there would be a
> tremendous propagation of error involved)?
>
> I'm asking about this because MM/PBSA calculations seem to offer a very
> nice advantage over other methods for determining say ligand binding energy
> (umbrella sampling, thermodynamic integration etc..) in that one can get
> these per residue decompositions of the energy terms, and thereby get a
> clue as to how the protein for instance, might be re-engineered for better
> binding, whereas methods like umbrella sampling would essentially require a
> guess, followed by another whole analysis of the mutated complex in order
> to test only one potential mutation.
>
> Thanks,
>
> ~Aron
>
> --
> Aron Broom M.Sc
> PhD Student
> Department of Chemistry
> University of Waterloo
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
--
++++++++++++++++++++++++++++++++++++++++++++++++++
Dr. Holger Gohlke
Professor fuer Pharmazeutische/Medizinische Chemie
Heinrich-Heine-Universitaet Duesseldorf
Institut fuer Pharm. und Med. Chemie
Universitaetsstr. 1
40225 Duesseldorf
Germany
Tel.: (+49) 211-81-13662; Fax: (+49) 211-81-13847
Email: gohlke.uni-duesseldorf.de
URL: http://cpclab.uni-duesseldorf.de
Book: "Protein-Ligand Interactions", Wiley-VCH
http://www.wiley-vch.de/publish/dt/books/forthcomingTitles/CH00/3-527-32966-8
++++++++++++++++++++++++++++++++++++++++++++++++++
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Sun Feb 17 2013 - 04:30:02 PST
