**From:** Shirley Hui (*shirleyhui_at_alumni.uwaterloo.ca*)

**Date:** Fri Apr 23 2004 - 15:30:01 CDT

**Next message:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Previous message:**Uday Chippada: "RE: Hi"**In reply to:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Next in thread:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Reply:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Messages sorted by:**[ date ] [ thread ] [ subject ] [ author ] [ attachment ]

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
*

*>
*

**Next message:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Previous message:**Uday Chippada: "RE: Hi"**In reply to:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Next in thread:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Reply:**Jérôme Hénin: "Re: Fw: Calculating Free Energy Change"**Messages sorted by:**[ date ] [ thread ] [ subject ] [ author ] [ attachment ]

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