[gmx-users] Entropy correction in PMF

[Ángel Piñeiro]

Thanks a lot Chris and Berk for your answers. I think that there are (at
least) two different and independent corrections that should be
performed to estimate absolute binding energies from the pmf (that is
indeed my aim) -the  correction for the reference state that depends on
the concentration of the different species in the solution (this is
quite clear in the Gilson's papers) and the entropic correction. I may
agree that whether or not the entropic correction should be performed
depends on what you want the pmf for.... but what is the difference
between a substrate-protein complex and the interaction between two
methane molecules in solution regarding the entropic correction?

My confusion comes from these two sentences in the manual:

"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."

Summing up my concern: Does the entropic term really contribute to the
absolute binding energy, or, on the contrary, this absolute  binding
energy must be calculated from the previously corrected pmf?

Angel.



On Thu, 2008-04-24 at 09:23 +0200, Berk Hess wrote:
> 
> 
> 
> 
> 
> 
> ______________________________________________________________________
> > Date: Wed, 23 Apr 2008 20:34:40 -0400
> > From: chris.neale at utoronto.ca
> > To: gmx-users at gromacs.org
> > Subject: [gmx-users] Entropy correction in PMF
> > 
> > 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?
> 
> This is not a simple should or should not.
> It depends on what you want to use the PMF for.
> 
> You should be aware that there is this simple entropic distance
> contribution.
> When a substrate needs to enter into a protein, it has to work against
> this entropic term. If you include this or not, depends on how your
> want
> to present the PMF in a presentation, or how your will use it for
> further
> calculation.
> 
> Berk.
> 
> 
> 
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