[gmx-users] large error bars in PMF

Justin A. Lemkul jalemkul at vt.edu
Mon Aug 1 13:18:39 CEST 2011 


Rebeca García Fandiño wrote:
> Hello,
> some days ago you had recomended me to use a dodecahedron box and 
> "pull_dim = Y Y Y"  to try to decrease some error bars I was obtaining 
> in my PMF calculations (trying to calculate the binding energy of two 
> cyclic peptides).
> Now, I have run these calaculations, but I have a doubt for the analysis.
> How should I analyze the results, using g_wham like in the case of 
> "pull_dim = N N Y". I have not seen any option in g_wham to indicate 
> this is a 3D PMF. I have also seen in this list these days that 3D-Wham 
> was recomended (for a case different to mine).
> So, how should analyze the results obtaind from "pull_dim = Y Y Y" ?

Just as you would previously.

-Justin

> Thanks a lot for your help.
> Best wishes,
> Rebeca.
> 
> ------------------------------------------------------------------------
> From: regafan at hotmail.com
> To: gmx-users at gromacs.org
> Subject: RE: [gmx-users] large error bars in PMF
> Date: Fri, 22 Jul 2011 12:41:34 +0000
> 
> I have used a cubic box of dimensions 8 x 8 x 14 (nm), and my total 
> pulling was 5nm along the z direction. I dont´t think there could be a 
> problem with the PBC, since the layer of solvent around the protein is 
> quite big, although I suppose that using a dodecahedron box for this 
> system would have been better.
> I will try now the "pull_dim = Y Y Y"  and see what it happens.
> Thanks a lot for the suggestions!
> Best wishes,
> Rebeca.
> 
>  > Date: Fri, 22 Jul 2011 08:23:18 -0400
>  > From: chris.neale at utoronto.ca
>  > To: gmx-users at gromacs.org
>  > Subject: [gmx-users] large error bars in PMF
>  >
>  > I see now what you mean. As it happens, I doubt that this would have
>  > caused the problem since no force was applied on X and Y dimensions,
>  > so it would require that there was a PBC-based distance degeneracy
>  > along Z, although this is of course possible and hopefully Rebecca
>  > will answer this part.
>  >
>  > Also, thanks for the pull_dimension/pull_vec fix.
>  >
>  > Chris.
>  >
>  > -- original message --
>  >
>  >
>  > chris.neale at utoronto.ca wrote:
>  >
>  > [Hide Quoted Text]
>  > I don't see why the box-type makes any difference whatsoever. It is
>  > possible that if you use a rhombic dodecahedron, you may reduce the
>  > system size, thus simulate more ns/day, thus converge faster, but that
>  > should be the only effect. I would be interested to hear more from
>  > Justin about how the box-shape is expected to affect peptide rotation...
>  > perhaps I misunderstand this point.
>  > My point was not that the box shape has any effect on protein 
> rotation. That
>  > will happen regardless of the box shape, of course. My suggestion for
>  > this box
>  > type was that since Rebeca has a system that is essentially spherically
>  > symmetric (i.e. two proteins connected by some arbitrary vector, 
> which are at
>  > the same time rotating freely), then she must use a suitable box 
> shape that
>  > reflects this type of symmetry. I never got a clear answer to whether 
> or not
>  > the weird interactions she cited were due to PBC or not, but if one 
> uses a
>  > rectangular box for a system like this one, there can be artificial
>  > interactions
>  > very easily.
>  >
>  > [Hide Quoted Text]
>  > I have a few other comments.
>  >
>  > 1. If you allow the peptide to rotate freely, then you do indeed need to
>  > converge all of their different rotational interactions. An alternative
>  > is to apply orientational restraints during the pulling (assuming that
>  > you know the bound state) and then to correct to an unrestrained state
>  > at large separations. You can see, for instance, D. L. Mobley, J. D.
>  > Chodera, K. A. Dill. "On the use of orientational restraints and
>  > symmetry number corrections in alchemical free energy calculations", ...
>  >
>  > 2. You are using "pull_dim = N N Y" which, if I haven't entirely
>  > forgotten how the pull-code works, means that the distance along Z is
>  > restrained but the distance along X and Y is free to change. What you
>  > end up with by sampling in this way is pretty strange and will require a
>  > really weird volumetric correction in the absence of infinite sampling
>  > time. You must decide to either: (i) pull to a spherical distance:
>  >
>  > pull_dim = Y Y Y
>  > pull_geometry = distance
>  >
>  > or (ii) to pull along a defined vector
>  >
>  > pull_dim = Y Y Y
>  > pull_geometry = direction
>  > Just a note here - if you set direction geometry, the pull_dim 
> keyword is not
>  > used, but pull_vec is.
>  >
>  > -Justin
>  >
>  > [Hide Quoted Text]
>  > What you have done:
>  >
>  > pull_dim = N N Y
>  > pull_geometry = distance
>  >
>  > is only really useful when the system is isotropic along the XY plane
>  > (at least in the time averaged sense), such as for a lipid bilayer, or
>  > when the freedom in X and Y is very low, such as in a channel.
>  >
>  > 3. Finally, just because you sampled *more* doesn't mean that your
>  > values are converged. Look into block averaging and test to see if your
>  > binding free energy is drifting over time.
>  >
>  > Good luck,
>  > Chris.
>  >
>  > -- original message --
>  >
>  > Hi again,
>  > I have one doub about the suggestion of using a dodecahedral box for my
>  > umbrella sampling to remove the problems I am having with the peptides
>  > rotating. I cannot see why a dodecaheral box is going to avoid this.
>  > Would it be better a truncated octahedron?
>  > Thanks a lot for your help.
>  > Best wishes,
>  > Rebeca.
>  >
>  > <... snip...>
>  >
>  >
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-- 
========================================

Justin A. Lemkul
Ph.D. Candidate
ICTAS Doctoral Scholar
MILES-IGERT Trainee
Department of Biochemistry
Virginia Tech
Blacksburg, VA
jalemkul[at]vt.edu | (540) 231-9080
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin

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