Re: Fw: Calculating Free Energy Change

From: Jérôme Hénin (
Date: Fri Apr 23 2004 - 15:00:25 CDT


> Brian,
> Thank you for your clarification.
> Yes, in my case, I would consider lambda = 0 as conformation 1 and lambda =
> 1 as the final conformation.
> I did come across the posting you sent me. My impression was that this
> tool takes as input a PDB style FEP file and spits out a PSF file which can
> then be sent into the *alchemical FEP* of NAMD.

That's correct.

> However, my problem does not involve any alchemical transformations of the
> molecule. This is what I am assuming...
> In the case of alchemical transformations, residues can mutate into other
> ones (i.e alanine to glycine etc).
> In the case of conformational changes, the molecule is simply undergoing a
> conformational change whereby the residues remain the same but the
> positions differ.
> Would the alchemcial function be suitable in my case, if there is no
> alchemical transformations taking place? Would one of the FEP algorithms
> mentioned in the user guide
> ( either MCTI
> or PMF approach be more suitable?
> I intend to create an FEP file with the initial coords corresponding to
> lambda = 0 and the perturbed coords corresponding to lambda =1.
> Then run the simulation for FEP calculation in NAMD using MCTI or PMF.
> ***If anyone knows that this is incorrect, please let me know!***

For a conformational change, the correct approach most probably is one of the
"conformational free energy" calculatiion methods, unless your problem can be
restated as one or several alchemical transformations, which does not seem to
be the case.

The applicability of the conformational methods will be limited by this
(quoted from the user's guide) : "The system is efficient if only a few
coordinates, either of individual atoms or centers of mass of groups of
atoms, are needed."

So your problem will be to design a - small - set of forcing restraints
(positions, distances, angles or dihedrals) that enforce the conformational
change you're interested in. For that purpose, no additional coordinate file
is used (FEPfiles are for alchemical FEP). Rather, the "fep" script specifies
the end-point values for each of the restrained coordinates.
Then, you can compute a PMF along your transformation pathway.
If the pathway is complex, you may want to cut the transformation into several

> My final question has to do with clarifying what all the conformational
> constraints mean:
>0 00000000000
> What is the difference between:
> Restraint Specifications (not coupled to pmf calculation) - is this only
> for mcti??
> Bound Specifications (not coupled to pmf calculation) - is this only for
> mcti??
No, it may be used with either mcti or pmf blocks. It just applies the
restraints you ask for, and does no further calculation.

> Forcing Restraint Specifications (coupled to pmf calculation) - only for
> pmf, related to the restraint potential??

These restraints together define the restraining potential, the derivative of
which is the basis for computing the free energy change, using either slow
growth ("pmf" keyword) or standard thermodynamic integration ("mcti"

> Are there some papers or text books that someone can recommend that I can
> read up on this?
"Computer Simulation of Biomolecular Systems", edited by van Gunsteren and
others ( gives a detailed overview of several
state-of-the-art free energy calculation methods.


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