Re: AMBER: Thermodynamic Integration for a CHARGED molecule

From: David Mobley <>
Date: Fri, 17 Aug 2007 06:56:33 -0700


There are two basic approaches to this problem, which is a tricky one:
(a) Use a treatment of long range electrostatics that will handle this
for you. (In my view this is a bit questionable, or at least a bit
difficult -- for example, some PME implementations will introduce a
uniform neutralizing background charge if the system is not net
neutral. Thus, if you begin with a net neutral system and turn off the
charge, the background charge will gradually turn on, keeping the
system net neutral, so it will "work" in some sense. Kastenholz and
Hunenberger have done some work on possible corrections that may need
to be applied to free enregies computed using this approach, in the
last couple years. I believe Gerhard Hummer also did some work on ion
solvation in the late 1990s that touched on this as well).
(b) Take a counterion with the ligand. That is, additionally decouple
a counterion. You will also need to do this for the ligand in solvent.
Then when you take the difference the ion solvation component should
cancel (if you do this carefully!) and you should just get the binding
energy. I'm not aware of anyone who has actually don this yet, though,
so you should think of it as a research project. Also, you will want
to be careful with the counterion to make sure it doesn't have
convergence problems -- perhaps keeping it in bulk, far away from the
ligand and receptor, as you disappear it. To avoid mucking with the
electrostatic environment of the receptor you may also want to use a
reasonable salt concentration so the counterion doesn't drastically
change the electrostatic environment as it's removed.

Another approach, of course, is to change your method for computing
the binding free energy and use a PMF-based method instead.

Let me know what happens -- this is something I'm interested in as
I'll certainly have to do this eventually. I'm leaning towards option

Best wishes,
David Mobley

On 8/17/07, ming hui <> wrote:
> Dear all,
> I am currently trying to calculate the free energy of binding of a molecule
> of Tris with charge=+1,
> with the double decoupling method that involves thermodynamic integration.
> When I am decoupling the electrostatic interactions of Tris from clambda=0
> to clambda = 1,
> how do I keep the system neutral?
> (since at the beginning I would need one Cl- ion, and at the end no ion
> would be needed)
> I would really appreciate any advice on this matter!
> Thank you.
> Regards,
> Ming Hui
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Received on Sun Aug 19 2007 - 06:07:40 PDT
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