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

Wed Nov 21 18:33:31 CET 2018

Or maybe perform the initial pull-simulation in the other direction as
well, and combine the results from the two simulations?

Den ons 21 nov. 2018 kl 18:30 skrev Gmx QA <gmxquestions at gmail.com>:

> 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
>> >>>>>>>
>> >>>>>>> ==================================================
>> >>>>>>>
>> >>>>>>> --
>> >>>>>>> Gromacs Users mailing list
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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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>> >>>> --
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>> >>>
>> >>> --
>> >>> Shreyas Sanjay Kaptan
>> >>> --
>> >>> Gromacs Users mailing list
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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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>