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 Thu Nov 05 2015 - 04:00:04 PST
