From: Chris Chipot (chipot_at_ks.uiuc.edu)
Date: Mon May 31 2010 - 10:29:53 CDT
Elio,
thinking that a single potential of mean force will give you the
correct binding free energy is not only wishful thinking, but it
is also wrong.
First, what is the proper direction along which the ligand should
be extracted from the binding pocket? Short of being clairvoyant,
I would say that different pathways have to be explored and properly
weighted. This is rather nicely documented in the following paper:
Standard Free Energy of Binding from a One-Dimensional Potential
of Mean Force. Doudou, S.; Burton, N. A.; Henchman, R. H. J. Chem.
Theory Comput. 2009, 5, 909–918.
Second, the binding free energy deduced from the crude potential of
mean force cannot be readily compared with experiment. It requires
standardization. A number of people, among whom B. Roux and colls.,
have discussed this issue in ample detail. The above paper addresses
it as well.
Third, there is a number of routes to measure free-energy differences.
Depending upon the nature of the problem, one method will be superior
to another. In the case of protein:ligand binding, where no one knows
what the actual reaction pathway is, I concur with Jerome - this is a
no-brainer: One should use alchemical transformations, which are better
suited for this problem. I am not saying, however, that this route is
an easy one. Relative binding free energies are by and large always
easier to evaluate than standard ones (see the 2009 centennial J. Phys.
Chem. B paper of Deng, Y. and Roux, B.).
Chris
Elio Cino wrote:
> Thanks Jérôme. I left the COM distance simulation run anyways. The
> output pmf does not match the experimental value. Sampling was good, but
> the outcome is not as expected. Do you know why ABF is not well suited
> for such systems? From what I was reading about the method it seems like
> it would be applicable for my system. Anyways, I appreciate your help on
> this. I have tried the alchemical TI method in gromacs before but had
> some problems and abandoned it for umbrella sampling, which has been
> partially successful. I think I will have to retry TI if I ever want a
> chance to reproduce an experimental delta G of peptide ligand binding to
> a protein.
>
> ----- Original Message -----
> From: Jérôme Hénin <jhenin_at_ifr88.cnrs-mrs.fr>
> Date: Saturday, May 29, 2010 8:16 am
> Subject: Re: namd-l: new NAMD user ABF setup question
> To: Giacomo Fiorin <giacomo.fiorin_at_temple.edu>
> Cc: Elio Cino <ecino_at_uwo.ca>, namd-l_at_ks.uiuc.edu
>
> > Hi Elio,
> >
> > My guess is that a COM-COM distance will not work well for
> > peptide/protein binding for any other method than irreversible
> > unbinding by SMD (which will not give you binding free energies except
> > on a qualitative level for comparison purposes).
> >
> > In general, binding free energies are best calculated by alchemical
> > means (see the alchemical free energy tutorials).
> >
> > Jerome
> >
> >
> > On 28 May 2010 16:03, Giacomo Fiorin
> > <giacomo.fiorin_at_temple.edu> wrote:
> > > Not exactly. ABF and umbrella sampling can be applied in
> > theory on the very
> > > same (reaction) coordinates. The reason why you needed to
> > define a specific
> > > direction for pulling apart the two proteins was (I think)
> > because of the
> > > way the Gromacs implementation was written, not the general umbrella
> > > sampling method.
> > >
> > > In the ABF implementation in NAMD, you can try first the COM-
> > COM distance,
> > > and maybe switch later to more sophisticated ones if you think
> > there is the
> > > need for. Also, since it's implemented within the colvars
> > module, you can
> > > even reuse the exact same variables/coordinates with ABF and
> > umbrella> sampling, and be able to compare their results, if
> > that's what you are
> > > interested in.
> > >
> > > Giacomo
> > >
> > > ---- ----
> > > Dr. Giacomo Fiorin
> > > ICMS - Institute for Computational Molecular Science - Temple
> > University> 1900 N 12 th Street, Philadelphia, PA 19122
> > > giacomo.fiorin_at_temple.edu
> > > ---- ----
> > >
> > >
> > >
> > > On Fri, May 28, 2010 at 8:48 AM, Elio Cino <ecino_at_uwo.ca> wrote:
> > >>
> > >> Thanks Giacomo. Very helpful reply. I think that I am
> > treating the ABF
> > >> setup too much like that for umbrella sampling where a
> > specific coordinate
> > >> is define. For ABF if I simply specify a range of COMdistance
> > between the
> > >> protein and ligand then I presume that conformations in this
> > defined COM
> > >> range will eventually be sampled. This way I do not need to
> > pull them apart
> > >> along a straight line, for example. Hopefully I have this
> > straight. Ill have
> > >> to read a bit more on ABF to be sure. Thanks again.
> > >>
> > >> ----- Original Message -----
> > >> From: Giacomo Fiorin <giacomo.fiorin_at_gmail.com>
> > >> Date: Thursday, May 27, 2010 5:27 pm
> > >> Subject: Re: namd-l: new NAMD user ABF setup question
> > >> To: Elio Cino <ecino_at_uwo.ca>
> > >> Cc: namd-l_at_ks.uiuc.edu
> > >>
> > >> > Hi Elio, the most intuitive collective variable, or
> > reaction coordinate
> > >> > is the COM-COM distance, whichever its direction may be.
> > If you want to
> > >> > pull them apart (and back together!) along a specific
> > direction, you have to
> > >> > restrict the variable to be on the projection along that
> > "specific>> > coordinate" as you said: do you mean Cartesian
> > coordinate (x, y or z)? My
> > >> > suggestion is to use distanceZ from the ABF implementation
> > in NAMD 2.7b1 and
> > >> > 2.7b2, and also define distanceXY with a restraint to be
> > zero, so that
> > >> > you'll have a straight line, if that's what you want.
> > >> >
> > >> > The comment you were referring to sounds specific to a well
> > defined>> > system, which may not be similar to yours. The
> > boundaries defining the
> > >> > relevant region of your system are your choice entirely.
> > >> >
> > >> > You should check out the ABF paper and compare it with
> > umbrella sampling
> > >> > using your own intuition. Too often comparisons between
> > free energy methods
> > >> > are based on specific examples that may not necessarily be
> > applicable to
> > >> > your case.
> > >> >
> > >> > In any case, when the variables are appropriately chosen,
> > ABF DOES give
> > >> > you an accurate PMF within the range (boundaries) you defined.
> > >> >
> > >> > Giacomo
> > >> >
> > >> > ---- ----
> > >> > Dr. Giacomo Fiorin
> > >> > ICMS - Institute for Computational Molecular Science - Temple
> > >> > University
> > >> > 1900 N 12 th Street, Philadelphia, PA 19122
> > >> > giacomo.fiorin_at_temple.edu
> > >> > ---- ----
> > >> >
> > >> >
> > >> >
> > >> > On Thu, May 27, 2010 at 3:10 PM, Elio Cino
> > <ecino_at_uwo.ca> wrote:
> > >>>
> > >>> > Hello. I have been trying to calculate free energies of
> > peptide binding
> > >>> > to a protein with umbrella sampling in gromacs with mixed
> > results. Anyways,
> > >>> > I was hoping the ABF method may help me get accurate
> > results faster than
> > >>> > umbrella sampling. I have read some of the ABF tutorial
> > and manual, but am a
> > >>> > bit confused about the ABF setup. I set the boundaries for
> > the COM distance
> > >>> > between the peptide and protein, but I think I need to
> > specify a direction
> > >>> > also since I want to pull the peptide away from the
> > protein along a specific
> > >>> > coordinate. I am unsure if they is correct, and if so how
> > to specify the
> > >>> > direction. Also, I read a comment saying that much of the
> > ABF calculation
> > >>> > time is spent climbing uphill to overcome the forces
> > (between peptide and
> > >>> > protein) at low COM distances and to avoid this, the lower
> > boundary should
> > >>> > be increased. Will this still provide an accurate PMF? It
> > seems that
> > >>> > excluding these low boundary states would cause some
> > errors in the delta G.
> > >>> > Any help is appreciated. Thanks.
> > >>> >
> > >>> > Elio Cino
> > >>
> > >> >
> > >>
> > >>
> > >> Elio Cino
> > >
> > >
> >
>
> Elio Cino
--
_______________________________________________________________________
Chris Chipot, Ph.D.
on leave from Nancy Université, CNRS
Theoretical and Computational Biophysics Group
Beckman Institute
University of Illinois at Urbana-Champaign
405 North Mathews Phone: (217) 244-5711
Urbana, Illinois 61801 Fax: (217) 244-6078
E-mail: chipot_at_ks.uiuc.edu
Christophe.Chipot_at_edam.uhp-nancy.fr
Web: http://www.ks.uiuc.edu/~chipot
http://www.edam.uhp-nancy.fr
I disapprove of what you say, but I will defend to the death your right
to say it
Evelyn Beatrice Hall
_______________________________________________________________________
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