# Re: Fw: Calculating Free Energy Change

From: Shirley Hui (shirleyhui_at_alumni.uwaterloo.ca)
Date: Fri Apr 23 2004 - 15:30:01 CDT

Hi,

You wrote:
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 stages.

You are right! There are no FEP files for the conformational free energy
calculations :P I think I got mixed up with the alchemical stuff.
So if I understand you correctly, I need to specify a set of restraints that
determine how my molecule will be 'perturbed'.
What I have right now is the original and perturbed coordinates only. I
don't know what kind of forces or restraints would be necessary for the
molecule to perturb from the original conformation to the final
conformation?? Is it possible to use NAMDs free energy calculator for
conformational perturbations in such a way if all you know are the original
and final coordinates?? I was reading the user guide and I wonder if
stating values for the bound specifications might achieve this (in which the
value of hi = (x,y,z), is the x,y,z coords of the perturbed conformation
(see below)?? To me it doesn't sound quite right though... If the
molecule is large, then the forcing constraints will be huge (since each
atom has a hi x,y,z bound constraint) and NAMD does not like this...

// 1. impose an upper bound if an atom's position strays too far from
a reference position.

urestraint {

posi bound (insulin, 3, cb) kf=20 hi = (2.0, 2.0, 2.0, 10.0)

}

thank you,
shirley

----- Original Message -----
From: "Jérôme Hénin" <jerome.henin_at_uhp-nancy.fr>
To: "Shirley Hui" <shirleyhui_at_alumni.uwaterloo.ca>; <namd-l_at_ks.uiuc.edu>
Sent: Friday, April 23, 2004 4:00 PM
Subject: Re: namd-l: Fw: Calculating Free Energy Change

> Hi,
>
> > 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.
> >
> > QUESTION ONE:
> > 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
> > (http://www.ks.uiuc.edu/Research/namd/current/ug/node33.html) 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
> stages.
>
> > QUESTION TWO:
> > My final question has to do with clarifying what all the conformational
> > constraints mean:
> >
http://www.ks.uiuc.edu/Research/namd/current/ug/node33.html#SECTION00097300
> >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"
> keyword).
>
> > 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 (http://www.wkap.nl/prod/s/CSBS) gives a detailed overview of
several
> state-of-the-art free energy calculation methods.
>
> Cheers,
> Jerome
>

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