Dear Fabian,
what you could try is "absolute" free energy simulation where you
completely "destroy" the ligand. This means you mutate it into nothing
and does get the solvation free energy. Have a look
into
http://pubs.acs.org/doi/abs/10.1021/ct400340s how to do that. The
SI of that paper describes how to prepare inputs with sample scripts.
Your ligands are very dissimilar anyway so computing relative free
energies by mutating them into each other may be problematic and
difficult to do. But you ligands are also very large so you should
carefully monitor if your free energy converges and also look into the
statistics.
Cheers,
Hannes.
On Thu, 19 Nov 2015 18:40:19 +0200
Fabian gmail <fabian.glaser.gmail.com> wrote:
> Dear Hannes,
>
> Sorry to bother you, I went through the A9 tutorial in detail, and I
> have several additional questions to my specific goals and molecules:
>
> I am not sure how to construct my thermodynamic cycle, in my case
> there is no protein, only two different ligands, for what I saw in
> your tutorial cycle, you need a protein medium to run MD and mutate
> the ligand. In my case the protein medium does not exist and the
> ligands are very big and quite different… I would prefer not to
> mutate them if possible.
>
> Another possibility for me would be to run two different type of
> solvents, one would be the ligand in pure water and the other in
> water + acetone for example and calculate the difference between the
> two ligands. And then I would calculate the DG of transfer between
> water to water + acetone or the hydration in water + acetone, which
> is very close to what really happens, Is this doable with TI?
>
> Additionally, the ligands I consider are very very flexible large and
> different see them:
>
> https://en.wikipedia.org/wiki/Darunavir
> <https://en.wikipedia.org/wiki/Darunavir>
> https://en.wikipedia.org/wiki/Ritonavir
> <https://en.wikipedia.org/wiki/Ritonavir>
>
> Can they be mutated into each other without accumulating charge
> errors?
>
> I think I would prefer not to mutate them but to calculate the
> hydration free energies of each of them in water and / or in water +
> acetone mixtures.
>
> Is that a good approach?
>
> Thansk a lot again,
>
> Fabian
>
>
> Dr. Fabian Glaser
> Head of the Structural Bioinformatics section
>
> Bioinformatics Knowledge Unit - BKU
> The Lorry I. Lokey Interdisciplinary Center for Life Sciences and
> Engineering Technion - Israel Institute of Technology, Haifa 32000,
> ISRAEL
>
> fglaser at technion dot ac dot il
> Tel: +972 4 8293701
> http://bku.technion.ac.il
>
>
> > On 17 Nov 2015, at 6:06 PM, Hannes Loeffler
> > <Hannes.Loeffler.stfc.ac.uk> wrote:
> >
> > On Tue, 17 Nov 2015 17:35:04 +0200
> > Fabian gmail <fabian.glaser.gmail.com> wrote:
> >
> >> Dear Hannes,
> >>
> >> Thanks a lot, it looks very interesting and relevant, my molecules
> >> are much larger (ritonavir and darunavir) but still I maybe able to
> >> use similar ideas.
> >
> > Regarding the number of atoms the following may be of use
> > https://mailman-1.sys.kth.se/pipermail/gromacs.org_gmx-users/2015-July/099194.html
> >
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Received on Thu Nov 19 2015 - 09:00:07 PST
