Dear Josh,
Thansk a lot, I am still trying to understand the details, but is this method applicable to a solvation calculation of free energy of such large and flexible molecules like ritonatvir and darunavir?
https://en.wikipedia.org/wiki/Ritonavir <
https://en.wikipedia.org/wiki/Ritonavir>
https://en.wikipedia.org/wiki/Darunavir <
https://en.wikipedia.org/wiki/Darunavir>
There are quite different…. that is the reason I think Hannes proposed to use a deletion approach, in which each one is removed from the solvent using TI and then the free energy calculated. Now I understand your method uses an hamiltonian but not quite how to use to calculate the free energy of solvation….
I want to calculate its solvation free energy in water (and also in water + acetone mixture) and compare it with another molecule… is that possible with emil?
Thanks a lot,
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 23 Nov 2015, at 9:24 AM, Josh Berryman <the.real.josh.berryman.gmail.com> wrote:
>
> Dear Fabian,
>
> If you are indeed considering absolute free energy calculation, for the
> reasons that Hannes advanced, then have a look at EMIL.
>
> starting point:
> http://ambermd.org/tutorials/advanced/tutorial19/
>
> This is an extension for TI in sander/pmemd intended to avoid the need to
> perturb all the way to nothing, allowing the user to instead perturb merely
> to a simplified version of the original Hamiltonian which is analytically
> tractable.
>
> Josh
>
>
>
> On 19 November 2015 at 17:54, Hannes Loeffler <Hannes.Loeffler.stfc.ac.uk>
> wrote:
>
>> 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 Mon Nov 23 2015 - 05:30:03 PST
