Re: [AMBER] What to expect when MD a peptide and a small organic molecule ?

From: Jason Swails <>
Date: Wed, 4 Nov 2015 09:01:04 -0500

On Wed, Nov 4, 2015 at 8:42 AM, Jean-Patrick Francoia <> 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).


Jason M. Swails
Rutgers University
Postdoctoral Researcher
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Received on Wed Nov 04 2015 - 06:30:03 PST
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