[gmx-users] Entropy correction in PMF

[David Mobley]

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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