**From:** Sterling Paramore (*gnilrets_at_gmail.com*)

**Date:** Tue Jun 26 2007 - 16:58:01 CDT

**Next message:**Victor Ovchinnikov: "Re: turn off intermolecular interaction"**Previous message:**JC Gumbart: "Re: turn off intermolecular interaction"**In reply to:**JC Gumbart: "Re: About pmf"**Next in thread:**Sting: "Re: About pmf"**Messages sorted by:**[ date ] [ thread ] [ subject ] [ author ] [ attachment ]

Another good paper on obtaining a PMF without invoking the stiff

spring approximation is Hummer and Szabo (2001) PNAS v98 p3658

On 6/26/07, JC Gumbart <gumbart_at_ks.uiuc.edu> wrote:

*> 1. Your point is well-taken; I also am worried from looking at that
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*> pmf that it is starting-point dependent. I do not know how they
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*> chose the points, although the paper by Wang, Tajkhorshid, and
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*> Schulten on AqpZ (I think) in Structure a couple years ago, which
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*> follows a similar procedure, might have more information.
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*>
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*> 2. I'm looking in the sixth window of figure 2c; it looks to me like
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*> the work peaks in that window.
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*>
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*> 3. Eq. 4 is not subtracting the energy in the spring. Eq. 4 is
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*> actually, I believe, exactly what you're proposing where dt*v is
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*> replaced by dx (because v = dx/dt) and f(t) by f(x). The energy in
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*> the spring is subtracting when going from the script W (eq. 4) to W,
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*> what's used in eq. 5, 6, 7, and 8.
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*>
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*> Here's the thing: that procedure gives you the PMF for the perturbed
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*> system, not the system without external forces which is what you
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*> want; this is pointed out in Eq. 3 of the Jensen paper. These two
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*> are usually equated by use of the "stiff spring" approximation where
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*> the ligand follows the imaginary point very closely. Since that
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*> wasn't the case for yours, it becomes more difficult to connect the
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*> PMF you calculate to the one you want. Please see the following two
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*> papers for more discussion on this point:
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*>
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*> 1) Park, Khalili-Araghi, Tajkhorshid, and Schulten. (2003) Free
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*> energy calculation from steered molecular dynamics simulations using
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*> Jarzynski's equality. JCP. 119: 3559-3566.
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*>
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*> 2) Park and Schulten. (2004) Calculating potentials of mean force
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*> from steered molecular dynamics simulations. JCP. 120: 5946-5961.
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*>
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*> In any case, I am pretty sure still that one simulation cannot give
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*> you an accurate pmf, I'm afraid. Using ABF (adaptive biasing forces)
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*> may work, although I've never tried it myself; see the NAMD manual
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*> for more on this.
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*>
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*> On Jun 25, 2007, at 9:38 PM, Sting wrote:
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*>
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*> > Hi JC Gumbart,
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*> > Thank you for your help!
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*> > But still there some question in my head.
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*> > 1. Can one just pull the ligand out only in one direction? How
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*> > they choose the start point for each SMD? I think the choosing for
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*> > the start point will eventually effect the profile of the external
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*> > work in fig2.C.
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*> > 2. I havn't see the highest point occurs in one of the reverse
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*> > direction. Since the forces in reverse directions is negative , the
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*> > work from cumulant will fall down accordingly.
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*> > 3. When computing the external work on ligand, the result from
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*> > formula 4 will substract the energy store in the 'spring'. Since in
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*> > our simulation, the center of mass of ligand deviates from the
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*> > pulling direction signicantly,can we just get the external work on
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*> > ligand by computing the inner product between the expulsion force
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*> > and the displacement vector of the center of the coordinates of the
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*> > ligand, and then employed the formula 6? If not, how can I get the
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*> > PMF correctly?
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*> >
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*> > Thank your for your time again! I really need your help.
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*> >
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*> >
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*> > Sting
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*> > stg1979_at_emails.bjut.edu.cn
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*> > 2007-06-26
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*> >
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*> > ==============
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*> >
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*> >> 1) Each SMD simulation started from an equilibrated point. To
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*> >> minimize the number of equilibration simulations needed, they pulled
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*> >> in opposite directions from each starting point.
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*> >>
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*> >> 2) I think so. I wouldn't say they had reduced work though; the
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*> >> highest point occurs in one of the reverse directions.
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*> >>
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*> >> 3) The procedure in the deca-alanine tutorial is the same as that in
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*> >> the paper in Eq. 7, both using the cumulant expansion of the average
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*> >> work. Eq. 8 is just a more complicated way of calculating <W> and
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*> >> <W^2>.
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*> >>
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*> >> On Jun 23, 2007, at 9:23 PM, Sting wrote:
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*> >>
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*> >>> Hi JC Gumbart,
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*> >>> sorry to disturb you again. As your suggestion, I read the paper
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*> >>> of Jensen et al.carefully, and in this paper I still have some
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*> >>> confusion:
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*> >>> 1. Why they performed SMD in two directions?
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*> >>> 2. It seems the most forces obtained from the inverse direction
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*> >>> are negative and these had reduced the works computed in Fig 2.b.
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*> >>> Do the negative values derive from the 'negative' direction?
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*> >>> 3. In this paper, a formula 8 was used, but I can not have any clue
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*> >>> from the tutorial 10Ala_tutor.
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*> >>> Since both the papers are from your group, they really puzzle me.
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*> >>>
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*> >>>
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*> >>> Thank you a lot!
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*> >>> ======= =======
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*> >>>
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*> >>>> I can attempt to answer but someone may correct me:
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*> >>>>
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*> >>>> 1) I'm pretty sure it would be the former, although it seems at
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*> >>>> least
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*> >>>> in our group that people calculate it slightly differently (but
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*> >>>> I am
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*> >>>> pretty sure both ways are equivalent). Please see some papers from
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*> >>>> our group for more specifics on this point (I'm looking at right
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*> >>>> now
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*> >>>> for instance Jensen et al. "Energetics of glycerol conduction
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*> >>>> through
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*> >>>> aquaglyceroporin GlpF").
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*> >>>>
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*> >>>> 2) The PMF is a force profile where as the activation energy is the
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*> >>>> amount of energy required to overcome the initial barrier. I do
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*> >>>> not
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*> >>>> know if the free energy of activation is different or not. I have
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*> >>>> never calculated a PMF myself, but one way to judge would be the
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*> >>>> size
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*> >>>> of the activation energy. 100 kJ/mol (~25 kcal/mol) does seem a
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*> >>>> bit
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*> >>>> large however and would likely only proceed if something else
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*> >>>> provided the energy or a conformational change took place (for
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*> >>>> comparison, thermal energy is only about 0.6 kcal/mol). One
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*> >>>> point I
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*> >>>> will make is that calculating accurate PMFs requires good sampling,
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*> >>>> so if you only ran one trajectory, it probably accumulated a large
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*> >>>> amount of irreversible work. Additional trajectories,
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*> >>>> appropriately
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*> >>>> averaged using Jarzynki's equality (again, papers from our group
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*> >>>> would be most helpful), may yield a lower number.
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*> >>>>
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*> >>>> More experienced people may feel free to chime in here. In any
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*> >>>> case,
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*> >>>> good luck!
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*> >>>>
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*> >>>>
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*> >>>> On Jun 18, 2007, at 11:00 PM, Sting wrote:
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*> >>>>
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*> >>>>> Hi all:
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*> >>>>>
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*> >>>>> I have performed a series of SMD with a constant velocity of 10
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*> >>>>> Å/
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*> >>>>> ns to force a ligand release from the binding pocket and try to
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*> >>>>> reconstruct the PMF, and I have some problem as follow:
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*> >>>>>
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*> >>>>> 1. How to compute the works done during the process? Should it be:
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*> >>>>> The displacement of ligand*applied Force or The displacement of
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*> >>>>> the
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*> >>>>> moving point which drag the ligand ?
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*> >>>>>
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*> >>>>> 2. What is the diffrence between the PMF and the Activation Energy
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*> >>>>> as well as that between it and the Free Energy of Activation, and
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*> >>>>> how to verify a reasonable PMF?
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*> >>>>>
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*> >>>>>
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*> >>>>> I really need someone to help me. Thank you in advance!
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*> >>
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*> > = = = = = = = = = = = = = = = = = = = =
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*> >
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*> >
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*> >
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*>
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*>
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*>
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**Next message:**Victor Ovchinnikov: "Re: turn off intermolecular interaction"**Previous message:**JC Gumbart: "Re: turn off intermolecular interaction"**In reply to:**JC Gumbart: "Re: About pmf"**Next in thread:**Sting: "Re: About pmf"**Messages sorted by:**[ date ] [ thread ] [ subject ] [ author ] [ attachment ]

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