[gmx-users] Non-symmetric PMF across lipid bilayer

Wed Nov 21 18:30:16 CET 2018

Hi Jochen

Thanks for your insights. That might possibly be the case, then? I need to
visualize my trajectory to find out I guess.
This is a cyclic peptide being pulled through the membrane, and the
reaction coordinate is indeed the com of the peptide with respect to the
membrane center.

 As I said, I (think I) understand the issues with convergence and slow
degrees of freedom, but I assumed initially that nevertheless my PMF should
be symmetric (but most likely not fully converged). Could one try to
restrain the water molecules somehow to keep them out, or is this simply a
problem of insufficient sampling that cannot be really solved without
adding a lot more simulation data?

/PK

Den ons 21 nov. 2018 kl 18:22 skrev Jochen Hub <jhub at gwdg.de>:

> Hi PK,
>
> I just looked at your PMF profile.xvg - you have a huge offset between
> the left and right end (140 kJ/mol), suggesting that you have a major
> problem with convergence. I would not use -cycl here - as such, I
> disagree here with the previous messages. :)
>
> -cycl is acceptable if your PMF looks more or less cyclic (no offset
> between left and right end). In that case, -cycl makes use of your
> knowledge that the PMF "should" be cyclic if you would simulate much
> longer. In other words: Witih -cycl, you get the most plausible PMF in
> the light of (i) your histograms and (ii) your knowledge that the PMF
> should be cyclic.
>
> I would instead try to find out *why* you have such a massive sampling
> problem. A reason could be that you have not used a good reaction
> coordinate (probably the COM of the solute wrt. the membrane?). Maybe
> you drag a lot of water into the membrane in the xi<0 region, but not in
> the x>0 region?
>
> Good luck,
> Jochen
>
> Am 21.11.18 um 15:49 schrieb Justin Lemkul:
> >
> >
> > On 11/21/18 9:03 AM, Gmx QA wrote:
> >> Hi Sheryas,
> >>
> >> Thanks - so are you saying that the PMF should be asymmetric with
> respect
> >> to the leaflets even before I make the PMF symmetric? This seems to
> >> contradict what Justin just said, but maybe you mean the same thing?
> >
> > I think we're saying the same thing, but I must correct an error I made.
> > I misremembered the WHAM option you need. It is not -sym (which
> > symmetrizes around zero), you need -cycl, which sets the end points to
> > be equivalent. This is effectively "symmetry" but with respect to the
> > end points, as I have been saying, rather than symmetry in the sense of
> > a "mirror image" at equivalent +/- values of the reaction coordinate.
> >
> > -Justin
> >
> >> Den ons 21 nov. 2018 kl 14:57 skrev Shreyas Kaptan
> >> <shreyaskaptan at gmail.com
> >>> :
> >>> I am reasonably sure that if the bilayer composition is asymmetric with
> >>> respect to leaflets you should see asymmetry in the PMF. In the ideal
> >>> case,
> >>> of infinite sampling, you should have zero free energy difference in
> the
> >>> bulk solvent for either side.
> >>>
> >>> On Wed, Nov 21, 2018 at 2:52 PM Gmx QA <gmxquestions at gmail.com> wrote:
> >>>
> >>>> Thanks again,
> >>>>
> >>>> So then to summarize: Using -sym is appropriate in this case, even
> >>>> though
> >>>> the bilayer is asymmetric with respect to lipid composition.  This
> fact
> >>>> would show up anyway (in the limit of unlimited sampling?)
> >>>>
> >>>>
> >>>>
> >>>> Den ons 21 nov. 2018 kl 14:44 skrev Justin Lemkul <jalemkul at vt.edu>:
> >>>>
> >>>>>
> >>>>> On 11/21/18 8:39 AM, Per Larsson wrote:
> >>>>>> Hi,
> >>>>>>
> >>>>>> Thanks Justin, but shouldn't the PMF be (more or less) symmetric
> >>>> anyway,
> >>>>>> given the inherent bilayer symmetry?
> >>>>>> In this case I have designed the two leaflets in the bilayer to have
> >>>>>> non-identical lipid composition, so then I think using -sym would
> >>>>>> obliterate any differences between the leaflets, no?
> >>>>> No, because that's completely unknown (and irrelevant) to WHAM. It
> >>>>> sets
> >>>>> the leftmost window to a zero energy and calculates every window's
> >>>>> energy relative to that, so you'll get the steady increase you see.
> If
> >>>>> you tell it that the leftmost and rightmost windows are equal (which
> >>>>> -sym), then the calculation proceeds differently.
> >>>>>
> >>>>> -Justin
> >>>>>
> >>>>>>
> >>>>>>
> >>>>>> On Wed, Nov 21, 2018 at 2:24 PM Justin Lemkul <jalemkul at vt.edu>
> >>> wrote:
> >>>>>>> On 11/21/18 7:22 AM, Gmx QA wrote:
> >>>>>>>> Hi all gmx-users
> >>>>>>>>
> >>>>>>>> I am working on calculating the PMF using umbrella sampling of a
> >>>>> (rather
> >>>>>>>> large) molecule across a lipid bilayer. I have set up my umbrellas
> >>>>> with a
> >>>>>>>> 0,2 nm spacing, and run each window for 100 ns.
> >>>>>>>>
> >>>>>>>> The problem is that the resulting PMF is not symmetric with
> respect
> >>>> to
> >>>>>>> the
> >>>>>>>> bilayer center. Initially is looks ok, but when the molecule is
> >>>> exiting
> >>>>>>> the
> >>>>>>>> bilayer on the other side again, the PMF does not go back to
> >>>> (roughly)
> >>>>>>> the
> >>>>>>>> same value as before entering the bilayer.
> >>>>>>>>
> >>>>>>>> I have uploaded the PMF file here:
> >>>>>>>> https://files.fm/u/7ec2rshc
> >>>>>>> You didn't get a symmetric profile because you didn't ask for one.
> >>> Use
> >>>>>>> the -sym option.
> >>>>>>>
> >>>>>>> -Justin
> >>>>>>>
> >>>>>>>> Any comments or suggestions are much appreciated. I understand the
> >>>>>>> problems
> >>>>>>>> and issues about calculations of a converged PMF with larger
> >>>> molecules,
> >>>>>>> but
> >>>>>>>> nevertheless I would have expected my PMF to be symmetric, albeit
> >>>>> perhaps
> >>>>>>>> not converged.
> >>>>>>>>
> >>>>>>>> Thanks
> >>>>>>>> /PK
> >>>>>>> --
> >>>>>>> ==================================================
> >>>>>>>
> >>>>>>> Justin A. Lemkul, Ph.D.
> >>>>>>> Assistant Professor
> >>>>>>> Office: 301 Fralin Hall
> >>>>>>> Lab: 303 Engel Hall
> >>>>>>>
> >>>>>>> Virginia Tech Department of Biochemistry
> >>>>>>> 340 West Campus Dr.
> >>>>>>> Blacksburg, VA 24061
> >>>>>>>
> >>>>>>> jalemkul at vt.edu | (540) 231-3129
> >>>>>>> http://www.thelemkullab.com
> >>>>>>>
> >>>>>>> ==================================================
> >>>>>>>
> >>>>>>> --
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> >>>>>
> >>>>> Justin A. Lemkul, Ph.D.
> >>>>> Assistant Professor
> >>>>> Office: 301 Fralin Hall
> >>>>> Lab: 303 Engel Hall
> >>>>>
> >>>>> Virginia Tech Department of Biochemistry
> >>>>> 340 West Campus Dr.
> >>>>> Blacksburg, VA 24061
> >>>>>
> >>>>> jalemkul at vt.edu | (540) 231-3129
> >>>>> http://www.thelemkullab.com
> >>>>>
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> >>>
> >>> --
> >>> Shreyas Sanjay Kaptan
> >>> --
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>
> --
> ---------------------------------------------------
> Dr. Jochen Hub
> Computational Molecular Biophysics Group
> Institute for Microbiology and Genetics
> Georg-August-University of Göttingen
> Justus-von-Liebig-Weg 11, 37077 Göttingen, Germany.
> Phone: +49-551-39-14189
> http://cmb.bio.uni-goettingen.de/
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