Ok, I'll dig deeper in the literature. Thank you all for your help.
Le 05/11/2015 12:38, Carlos Simmerling a écrit :
> I don't think the answer is that you must use explicit solvent. I think the
> real answer is that this is extremely challenging, and only a few articles
> have been published where this is shown reliably. The DE Shaw work required
> vast computer resources.
>
> I would say to try to find examples and see how they succeeded - it may be
> that standard, brute force MD won't work for you. This is a *very* hard
> problem, especially with a flexible peptide.
>
> On Thu, Nov 5, 2015 at 4:37 AM, Jean-Patrick Francoia <
> jeanpatrick.francoia.gmail.com> wrote:
>
>> Thank you, that was a very clear answer.
>>
>> I actually used igb=1 (because almost all the tutorials on the Amber
>> website use this setting). I will change it for igb=8 in the future.
>>
>> "
>>
>> GB simulations are infinitely dilute. It doesn't matter how strongly two
>> molecules bind, basic stat thermo tells you that the bound state of an
>> infinitely dilute solution is not stable, regardless of binding strength.
>> Remember that free energies of binding have an entropic component, and as a
>> result depend on concentrations (which are really just probabilities).
>>
>> If the system*starts* bound, then a strongly bound complex will take a
>> long time to dissociate, but expecting the small peptide to "capture" the
>> ligand molecule in implicit solvent may be overly optimistic, unless it
>> starts out "almost" captured.
>>
>> By contrast, explicit solvent calculations have a well-defined (and often
>> high) concentration, so you can actually expect to see binding events
>> sometimes (D. E. Shaw's research group has done some of this)."
>>
>>
>> Ok, I didn't think at all about the dilution. So basically, when you are
>> trying to see binding events, the general recommendation is to use
>> explicit solvent.
>> Do I understand well ? So binding events -> definitely no implicit solvent
>> ?
>>
>> In my case, I can't start with an "almost" captured ligand, because I'm
>> trying to find out how the two molecules bind.
>>
>> Le 04/11/2015 15:01, Jason Swails a écrit :
>>> On Wed, Nov 4, 2015 at 8:42 AM, Jean-Patrick Francoia <
>>> jeanpatrick.francoia.gmail.com> wrote:
>>>
>>>> Hello,
>>>>
>>>> I'm trying to do MD on a system made of a short peptide and the molecule
>>>> of cocaine. It is just a training. The peptide is a hexapeptide
>>>> (QHWWDW), easily generated with the 'sequence' command of xleap. The
>>>> library for the cocaine residue was built using antechamber.
>>>>
>>>> I merged the peptide and the cocaine. I performed a short minimization
>>>> using implicit solvent, and then, I tried to run a molecular dynamic. It
>>>> "worked", meaning the MD completed without errors. I now have a splendid
>>>> trajectory (1 ns). But I don't know what it means, and what to expect.
>>>>
>>> "Using implicit solvent" is about as specific as saying "using the Amber
>>> force field". There are many implicit solvent models, some more accurate
>>> than others (by a wide margin). The most modern GB model, and the one
>> that
>>> is probably the most accurate compared to explicit solvent calculations,
>> is
>>> igb=8 with mbondi3 radii. I would recommend using this combination.
>>>
>>>
>>>
>>>> I know the peptide and the cocaine bind "strongly" (I can't quantify
>>>> strongly). There are experimental evidences. So I was expecting the
>>>> peptide would fold and catch the cocaine, and that at some point, the
>>>> complex would stop changing. I was hoping to see a particular
>>>> conformation of the complex. Instead, I see the two molecules
>>>> interacting, but no preferred conformation (ok, maybe one, appearing
>>>> sometimes), but nothing really fixed.
>>>>
>>>> Was I right to expect that, or not ?
>>>>
>>> GB simulations are infinitely dilute. It doesn't matter how strongly
>> two
>>> molecules bind, basic stat thermo tells you that the bound state of an
>>> infinitely dilute solution is not stable, regardless of binding strength.
>>> Remember that free energies of binding have an entropic component, and
>> as a
>>> result depend on concentrations (which are really just probabilities).
>>>
>>> If the system *starts* bound, then a strongly bound complex will take a
>>> long time to dissociate, but expecting the small peptide to "capture" the
>>> ligand molecule in implicit solvent may be overly optimistic, unless it
>>> starts out "almost" captured.
>>>
>>> By contrast, explicit solvent calculations have a well-defined (and often
>>> high) concentration, so you can actually expect to see binding events
>>> sometimes (D. E. Shaw's research group has done some of this).
>>>
>>> HTH,
>>> Jason
>>>
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Received on Fri Nov 06 2015 - 02:30:03 PST
