Re: question about total charge change in FEP calculation

From: Chris Chipot (
Date: Sun Mar 05 2006 - 05:04:43 CST

The issue of total charge variation in the course of a
free energy calculation is a tricky one. It is rather
well documented in:

Donnini, S., A. E. Mark, A. H. Juffer, and A. Villa. 2005.
Incorporating the effect of ionic strength in free energy
calculations using explicit ions. J. Comput. Chem. 26:115-122.

and to a lesser extent in our recent:

Hénin, J., B. Maigret, M.Tarek, C. Escrieut, D. Fourmy, and
C. Chipot. 2006. Probing a model of a GPCR/ligand complex in
an explicit membrane environment: The human cholecystokinin-1
receptor. Biophys. J. 90:1232-1240.

If you decide to use counter-ions that will vanish or appear
through the simulation, pay attention that they do not come
exceedingly close to the perturbed titrable sites, as this
may lead to pseudo-non-ergodicity events. Whereas reversible
binding of counter-ions to titrable residues is a natural
thing to expect in "real life", repeated association and
dissociation is difficult to capture on the time scales
explored by MD - the ionic pairs appearing to persist
indefinitely. One possible way around it is to fix or
restrain the counter-ions spatially, to prevent them to
come too close to the perturbed titrable sites.

Chris Chipot wrote:

>Anyone has some experience with FEP and total charge change during the simulation, please give me some advice and share some experience.
>I would like to perform a free energy perturbation calculation in NAMD. It's a simple mutation to the cofactor of the protein. However, the total charge of the protein+cofactor system changed (from 6+ to 4+). So the beginning and ending structures would have different number of counter-ions. How should I handle such charge change in FEP calculation?
>Thanks a lot!

Chris Chipot, Ph.D.
Equipe de dynamique des assemblages membranaires
Unité mixte de recherche CNRS/UHP No 7565
Université Henri Poincaré - Nancy 1 Phone: (33) 3-83-68-40-97
B.P. 239 Fax: (33) 3-83-68-43-87
54506 Vandoeuvre-lès-Nancy Cedex


      To sin by silence when we should protest makes cowards out of men
                                                    Ella Wheeler Wilcox

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