Re: Question on making 'reversible' solvated simulation

From: Jérôme Hénin (
Date: Sun Feb 11 2018 - 04:56:22 CST

Hi Randy,

While adding a barrier to entry for water molecules may well make the
simulation more reversible, it will also make it biased and give an
overestimated binding affinity, by killing the binding site desolvation

It's a tough problem, but ideally this solvation/desolvation process needs
to be sampled.

Improving the sampling of that kind of "orthogonal" process was the focus
of some work by Wei Yang:

But that's only implemented in CHARMM afaik. The theory is somewhat

So I'm sorry to say, if it's a common problem, there is no universal,
simple and consensual approach to it.


On 10 February 2018 at 19:15, Randy J. Zauhar <>

> Hi,
> I am running a ligand annihilation in a solvated system, and I would like
> to make it truly reversible if possible.
> Issue is that a couple water molecules sneak into the active site when the
> ligand disappears. Then when I reverse and start creating the ligand, they
> are trapped.
> A simple thing I will try is to constraint the water molecules close to
> the active site, hopefully creating a barrier to entrance.
> However. this has to be a pretty common problem, is there a recommended
> approach to address it?
> Thanks!
> Randy
> Randy J. Zauhar, PhD
> Prof. of Biochemistry
> Dept. of Chemistry & Biochemistry
> University of the Sciences in Philadelphia
> 600 S. 43rd Street
> Philadelphia, PA 19104
> Phone: (215)596-8691
> FAX: (215)596-8543
> E-mail:<>
> “Yeah the night is gonna fall, and the vultures will surround you /
> And when you’re lookin’ in the mirror what you see is gon’ astound you"
> — Death Cab for Cutie, “Monday Morning"

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