[gmx-developers] more on electrostatic decoupling

[Michael Brunsteiner]

David,

I read your mail with some interest since I plan to use
Gromacs for binding free energy calculations including
charged ligands. What you write seems to suggest that
this cannot esily be done with the current Gromacs 
implementation (correct me somebody if i am wrong!)
I believe that most of your questions have been
answered in the literature (see my comments below) though
I wonder in how far the Gromacs developers are aware of these 
issues ...

--- David Mobley <dmobley at gmail.com> wrote:
> And currently, GROMACS requires that restraints be *within*
> the same "molecule"; that is, the ligand and protein
> must be defined in the same molecule section in order to 
> restrain the ligand to the protein.

not if you use the pull code for your restraints ...

> [...] that this means that the ligand will have long range
> interactions with copies of itself in vacuum. This appears 
> very problematic, actually: Here are two specific
> problems we've thought of based on Berk's line of reasoning:
> 1) If the ligand has a dipole moment, there will be long
> range dipole-dipole interactions between the ligand and
> copies of itself which will result in both forces and probably
> significant contributions to the energy. 

... not really, if the Ewald sum (or PME) is implemented
correctly - for a good overview of ALL terms see e.g.:
http://www.earth.ox.ac.uk/~keithr/moldy-manual/node11.html
There are two terms called "Uniform Sheet Correction"
and "Surface Dipole Term" - I am not sure if the former is 
in gromacs, however both terms need to be implemented
and understood (I am not sure if I do) in order to deal 
with systems with a permanent net-charge and/or dipole moment.
... you also might want to read:
S. Boresch and O. Steinhauser 
Presumed versus real artifacts of the Ewald summation 
technique: The importance of dielectric boundary conditions. 
Ber. Buns. Ges. 101:1019, 1997.

> 2) Problems will be box-size dependent. In binding free
> energy calculations,

there are (simple) correction terms that should be able
to do away with these problems. There are some papers 
by Gerald Hummer and others on the consistent calculation of 
free energies
e.g.: 
J. Phys. Chem., 100 (4), 1206 -1215
Free Energy of Ionic Hydration
Gerhard Hummer, Lawrence R. Pratt, Angel E. García
... and a number of follow ups.

There is also the following paper (this solution has a bit of 
an "ad-hoc" flavour though, and I am not sure whether their
remedy is necessary at all if the Ewald sum is implemented
correctly ... hope i don't step onto anybodies toes here ...):
S. Bogusz, T. E. Cheatham, III & B. R. Brooks.
Removal of pressure and free energy artifacts in charged 
periodic systems via net charged corrections to the Ewald 
potential.
J. Chem. Phys. 108, 7070-7084 (1998)

regards,
Michael


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