[gmx-users] Entropy correction in PMF

[Ángel Piñeiro]

Thank you David,
what you are suggesting is indeed a difference between substrate-protein
and methane-methane that seems more clearly related with the entropic
correction. If I understood well, what you mean is that the space
accessible to a ligand when it is pulled into a protein is restricted by
the interactions of the ligand with the protein atoms that form the 
pocket. However I think that the entropic correction should still stand
in some way... it could be a correction with non-spherical symmetry,
probably a cylindrical symmetry could work as an approach if the
coordinate for the pmf was just the distance between the two molecules
instead of, for instance, a vector in the z direction.

On the other hand I don't see a clear connection between this and the
concentration. The absolute concentration of ligand, protein and complex
is of course important to correct for the reference state but the
entropic correction appears to be independent... As you mention the
definition of the complex -that is another item to take into account-
could seem to be more related to the entropic correction but I think it
is also an independent effect because, even when you have a reasonable
method to define the complex and the restriction to the motion of the
ligand into the pocket exists, there is a certain freedom to move
laterally at each distance.

These are my conclusions but I am not sure I am right...

Angel Piñeiro.





On Thu, 2008-04-24 at 15:34 -0700, David Mobley wrote:
> Chris,
> 
> I think you are correct here. For binding calculations there is
> probably a further trick relating to how to define an unbound state
> that has a well-defined concentration. This I think depends on how one
> is pulling -- i.e. doing simple radial PMFs is probably a bad idea,
> because to even converge the PMF when the ligand is separate from the
> protein, you by definition need to integrate over all x, y, and z at
> that r, so you end up needing to sample a spherical shell covering a
> substantial fraction of the simulation box. For this reason I think
> it's probably wiser to do pulling along a specified vector away from
> the protein, for example (this is what people using this strategy have
> mostly done, I think). Additionally there is the standard state issue,
> which is important also.
> 
> I think you may have more or less raised all of these issues already;
> I'm just trying to put them a slightly different way.
> 
> David
> 
> 
> On Wed, Apr 23, 2008 at 5:34 PM,  <chris.neale at utoronto.ca> wrote:
> > That sentence could definitely use some massaging. Try this:
> >
> >  Whether one needs to correct for this contribution depends on what the
> >  pmf should represent. When one wants to pull a substrate into a protein,
> >  this entropic term indeed contributes to the work to get the substrate
> >  into the protein. This is because the work required to pull a ligand into a
> > protein binding pocket depends on the concentration of that ligand in the
> > unbound state. The entropic contribution, however, depends on the size of
> > your simulation box if your sampling of the entire box is ergodic. Further,
> > the large computational cost of converging the sampling of large separations
> > between the protein and ligand make it undesirable to target true ergodicity
> > for large separations. It is more efficient to calculate the work required
> > to pull a ligand into a protein from an unbound state that has a defined
> > concentration and then to separately calculate the work required to change
> > that concentration to some standard state, e.g. 1 molar.
> >
> >  If any other free energy users care to comment, perhaps we could come up
> > with something based on what I have suggested (or something entirely
> > different) that could go into the new manual.
> >
> >  --original message --
> >
> >  I sent the attached message on last March 31 but I didn't get any
> >  answer... may be the right people was not available at that time and
> >  that is why I am trying again. I would thank a lot to have some more
> >  detail about this paragraph in the gromacs manual (version 3.3, chapter
> >  6, page 111):
> >
> >  Whether one needs to correct for this contribution depends on what the
> >  pmf should represent. When one wants to pull a substrate into a protein,
> >  this entropic term indeed contributes to the work to get the substrate
> >  into the protein. But when calculating a pmf between two solutes in a
> >  solvent, for the purpose of simulating without solvent, the entropic
> >  contribution should be removed. Note that this term can be significant;
> >  when at 300K the distance is halved the contribution is 3.5 kJ mol-1."
> >
> >  why exactly for a substrate-protein complex shouldn't one correct the
> >  pmf?
> >
> >
> >
> >
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