Re: FEP charge perturbation

From: Chris Chipot (Christophe.Chipot_at_edam.uhp-nancy.fr)
Date: Fri Jun 03 2005 - 12:08:13 CDT

Dear Floris,

unfortunately, there is no easy answer to your question. By and large,
we haven't a sufficiently solid historical background to assert one
way or another. In the scenario that you describe, there are pretty
much two routes available: Either (a) you include a counter-ion that
will appear as glutamine is mutated into glutamate, or (b) you ignore
this change of the net charge in the box and rely on a possible
compensation of the latter by a background charge. So far, I have
failed to understand whether or not the NAMD implementation of PME
will handle the variation of the net charge in the course of the
simulation, and have, therefore, opted for the safer route (a). Yet,
if you go for this choice, be aware that the counter-ion may come
close to your perturbed residue and possibly bind to it, thereby
modulating the resulting change in free energy as lambda goes from 0
to 1. In fact, in a recent issue of J. Comput. Chem. (2005, 26,
115-122) Donnini et al. have advocated to avoid the use of
counter-ions that can lead to serious sampling issues. One, unphysical
way to circumvent this difficulty, would be to place the counter-ion
far enough from the mutated site, and prevent it from approaching the
latter by means of harmonic restraints or simply by keeping it fixed
in space.

Chris Chipot

Floris Buelens wrote:

>Hello,
>
>I'm running FEP where I'm trying initially to
>calculate the free energy difference between two bound
>peptides differing in one position, one glutamate, one
>glutamine.
>For my thermodynamic cycle, I'm simulating the 11-mer
>peptide in solution, but I'm unsure how to handle the
>change in charge between the two forms. When going
>from the glutamine-containing peptide (no net charge)
>to the glutamate one (net -1), should I introduce a
>compensatory cation?
>I've found some discussion of this in the literature
>but I'd appreciate comments if anyone has experience,
>Thanks for your time,
>
>Floris Buelens
>
>Crystallography, Birkbeck College, London
>
>
_______________________________________________________________________

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
                            E-mail: Christophe.Chipot_at_edam.uhp-nancy.fr
                                           http://www.edam.uhp-nancy.fr

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

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