Thanks for the suggestions Holger!
It seems the preference is on the second method owing to the need in the
first recalculate things repeatedly? But perhaps there is more to it, I'll
have a look at the recommended articles, thanks for taking the time to
respond.
~Aron
On Sun, Feb 17, 2013 at 7:01 AM, Holger Gohlke <gohlke.uni-duesseldorf.de>wrote:
> 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
>
--
Aron Broom M.Sc
PhD Student
Department of Chemistry
University of Waterloo
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Received on Sun Feb 17 2013 - 04:30:03 PST
