[gmx-users] Can g_wham support using different temperature for different windows?
Justin A. Lemkul
jalemkul at vt.edu
Tue Feb 22 14:10:08 CET 2011
Jianguo Li wrote:
> Thanks Justin and Chris and sorry for confusing interpretation.
> Let me make it more clear. My peptide is flexible Martini beads, and
> highly positively charged. My membrane is a mixture of negatively
> charged lipids (25%) and zitterionic lipids(75%). So there is strong
> electrostatic attraction
> between peptide and membrane. To get the PMF, I did the following:
>
> (1) I did pulling simulation along (0 0 -1) direction to pull my peptide
> across the membrane. Then I got different configurations corresponding
> to different windows along the reaction coordinates, which is the
> z-distance
> between peptide and membrane. This figure
> (http://www.flickr.com/photos/lijg/5467080971/) shows some of the
> configurations at certain reaction coordinates.
>
Are you not sampling configurations outside of the membrane (i.e. in water)? I
would think that would solve your problem. You don't show any configurations in
which the peptide is completely dissociated from the membrane. I don't know
your objectives, but I would think that if you could completely extract the
peptide from the membrane after passing through it, this would solve your problem.
> (2) In each window, I used the corresponding configuration that
> generated by the pulling simulation as initial input and run umbrella
> sampling. The size of each window is 0.15 nm, but close to the bilayer
> cneter (e.g., -0.6<d<0.6), I have
> increased number of windows so that the width of the window is to be
> 0.05 or 0.1 nm, I also tried to use different force constant in these
> windows.
>
> From the figure (http://www.flickr.com/photos/lijg/5467080971/) , we
> can classify the peptide conformation to be either extended (interacting
> with two bilayers) or compact (interacting with only one bilayer).
> Ideally, the peptide conformation should be similar for d=x and d=-x.
> The problem is that the configuration of peptide is not symmetric with
> respect to the bilayer center. For example, the peptide configuration is
> compact at d=0.6 and d=0.9, but the peptide is extended at d=-0.6 and
> d=-0.9. This leads Hysteresis. If I use g_wham to generate PMF, then the
> PMF is not symmetric with respect to the bilayer center. Using more
> number of windows and different force constant did not remove the problem.
>
> In my opinion, at least in some windows, the peptide should sample both
> compact and extended structure. But what I found is that the windowed
Don't pre-judge the model :) Also, as I said before, there is no reason to
suspect that MARTINI will produce any meaningful secondary structure changes.
It was not parameterized to do so.
> umbrella simulation depends on the initial peptide conformation. If the
> initial peptide conformation is compact, then after 100 ns, it is still
> compact; if the initial peptide in that window is extended, the final
> configuration is also extended. I also tried to run longer equilibrium
> time (e.g., 200 ns), but the problem still exists.
>
Sounds like a limitation of the force field model.
> My question is how to increase sampling of the peptide conformation? I
> just think of two choices:
> (1) use high temperature (e.g., 500K) at those bad windows. As I
> mentioned, I am wondering if g_wham can unbias the effect of using
> different temperatures in different windows.
> (2) use REMD in those bad windows. These need a lot of computational
> resources.
>
Neither of these will be useful in generating a sensible PMF curve. WHAM needs
a single temperature for proper weighting. If you start including different
temperatures in different regions of phase space, I would imagine the weighting
would be completely incorrect.
Note that SMD is not the only option for generating starting configurations. If
you think that certain orientations or configurations are "correct," you can
build them yourself, but keep in mind that you'll have to justify this procedure
to a skeptical audience.
-Justin
> Is there any other method to deal with the insufficient sampling?
> Any suggestions are welcome, thanks for your time reading this email!
>
> Cheers,
> Jianguo
>
>
> ------------------------------------------------------------------------
> *From:* Justin A. Lemkul <jalemkul at vt.edu>
> *To:* Gromacs Users' List <gmx-users at gromacs.org>
> *Sent:* Tuesday, 22 February 2011 11:13:05
> *Subject:* Re: [gmx-users] Can g_wham support using different
> temperature for different windows?
>
>
>
> Jianguo Li wrote:
> > Thanks for your comments, Justin.
> >
> > Using timestep of 20 fs, in each window the simulation runs for 100
> ns CG time. The pulling rate is 0.001 nm/ps. Is it too fast?
> >
>
> Let me clarify things, since I'm not convinced I understand your procedure.
> You generate a series of configurations with 0.001 nm/ps pulling, but
> then how many windows do you generate for independent simulations? What
> are your .mdp parameters during those windows? The pull rate should be
> 0 during the actual umbrella sampling, to restrain the peptide within
> the window. What force constant(s) do you use?
>
> > My system is a little different. My peptide is highly positively
> charged. The NMR experiments show that the conformation of the peptide
> in water is very dynamic, so I make it flexible without fixing any
> secondary structure in Martini model.
>
> As was discussed in the last few days, do not interpret changes in
> structure too directly when using MARTINI. It is not designed to
> faithfully mimic secondary structure changes.
>
> > In the membrane, 25% of the lipids are negatively charged, so there
> are very strong electrostatic attraction between peptides and membrane.
> >
> > During the peptide approaching the membrane from the top, peptide can
> take different configurations at different reaction coordinates. When
> pulling the peptide into the membrane, the peptide takes relatively
> compact structure and interacts with only the top leaflet until the
> distance becomes smaller than 0.45 nm, after that the peptide becomes
> extended structure and interacts with both leaflets. This extended
> structure remains until the distance becomes -1.05 nm. Further pulling
> leads to compact structure and interacts only with the lower leaflet. So
> the comformation of the peptide is not symmetric between the center of
> the bilayer, which leads to Hysteresis. It seems that there is a huge
>
> I guess I'm confused here, too. The peptide is compact when interacting
> with the top leaflet, extended further in the membrane, then compact
> again when interacting with the lower leaflet. What's strange about that?
>
> > energy barrier for the peptide to translocate across the membrane
> because if the initial conformation in a certain window is extended
> (interacting with both leaflets), then it remains extended. Similarly,
> it the initial conformation in a certain window is compact (interacting
> with only one leaflet), it will remain compact.
> >
>
> I don't see how that is necessarily unexpected or problematic. Peptides
> will change conformation depending on their environment. If you want a
> static structure to cross the membrane (which may or may not represent
> reality) you'll have to introduce some kind of intramolecular restraints.
>
> -Justin
>
> > Any Suggestions of dealing with the highly charged system?
> >
> > Cheers,
> > Jianguo
> >
> >
> > ------------------------------------------------------------------------
> > *From:* Justin A. Lemkul <jalemkul at vt.edu <mailto:jalemkul at vt.edu>>
> > *To:* Gromacs Users' List <gmx-users at gromacs.org
> <mailto:gmx-users at gromacs.org>>
> > *Sent:* Tuesday, 22 February 2011 09:58:36
> > *Subject:* Re: [gmx-users] Can g_wham support using different
> temperature for different windows?
> >
> >
> >
> > Jianguo Li wrote:
> > > Thanks Justin.
> > > I tried your suggestions by either increase more windows and
> change the force constant, but it seems the samplings are still bad in
> some windows. When I did pulling in (0 0 1) direction and a reverse
> pulling in (0 0 -1) direction, I got different configurations at certain
> reaction coordinates. And the windowed umbrella sampling seems depends
> strongly on the initial configurations in that window. Therefore I got
> different PMFs using pulling in (0 0 1) direction and reverse pulling in
> （0 0 -1) direction.
> > >
> >
> > How long are each of the simulations in each window? Sufficient
> sampling should eliminate any configurational bias and/or hysteresis.
> Also, if the pulling that sets up the initial configurations is done
> slowly enough, you won't see these problems. Sounds to me like you're
> pulling too fast or hard, such that the system is not stable.
> >
> > > In my simulation, I exert constraints on phosphate atoms in z
> direction, so there is no lipid flip-flop and the membrane will be
> stable at high temperatures. Then I am thinking of increasing
> temperature in those bad windows to enhance sampling...
> > >
> >
> > I don't know if I can make a convincing argument here, but
> intuitively, these windows would be sampling in a different ensemble, so
> the free energy landscape in these windows would be discontinuous with
> any adjacent windows that are done at different temperatures, and
> perhaps the forces required to restrain your peptide at a given COM
> distance will still result in a discontinuous PMF. I would also suspect
> that g_wham can't handle this situation; it has a -temp flag, but it
> only takes one value. So if you construct your PMF curve using WHAM,
> but supply incorrect or inconsistent information, I certainly wouldn't
> believe the result.
> >
> > I guess the main point is, there are tons of published demonstrations
> of peptides and other molecules crossing a membrane with SMD and
> umbrella sampling, so it should be possible to generate stable
> configurations without any funny tricks.
> >
> > -Justin
> >
> > > best regards,
> > > Jianguo
> > >
> > >
> > >
> > >
> ------------------------------------------------------------------------
> > > *From:* Justin A. Lemkul <jalemkul at vt.edu <mailto:jalemkul at vt.edu>
> <mailto:jalemkul at vt.edu <mailto:jalemkul at vt.edu>>>
> > > *To:* Discussion list for GROMACS users <gmx-users at gromacs.org
> <mailto:gmx-users at gromacs.org> <mailto:gmx-users at gromacs.org
> <mailto:gmx-users at gromacs.org>>>
> > > *Sent:* Tuesday, 22 February 2011 09:35:37
> > > *Subject:* Re: [gmx-users] Can g_wham support using different
> temperature for different windows?
> > >
> > >
> > >
> > > Jianguo Li wrote:
> > > > Dear all,
> > > >
> > > > I want to get the PMF of my peptide across the membrane
> bilayer. First I pulled my peptide across the membrane and then did
> windowed umbrella sampling along the reaction coordinates which is the
> z-distance between peptide and membrane. However, I found that sampling
> is not sufficient in some windows(e.g., around the center of the
> membrane). To enhance the sampling, I am thinking to run the simulation
> in those windows at higher temperature (e.g., 500K), but this will
> introduce a bias. My question is: can g_wham remove the bias due to
> using different temperatures in different windows?
> > > >
> > > > If g_wham cannot deal with the bias due to using different T, I
> may need to do REMD in those windows. But that will be very expensive
> computationally. Anybody have an idea of enhancing sampling in those
> windows?
> > > >
> > > > Btw, I am using Martini CG model.
> > > >
> > > > Any suggestions will be highly appreciated, thank you!
> > > >
> > >
> > > A more straightforward approach is to (1) add more sampling
> windows or (2) increase the force constant in regions where there's poor
> sampling, or perhaps both.
> > >
> > > -Justin
> > >
> > > > Cheers,
> > > > Jianguo
> > > >
> > >
> > > -- ========================================
> > >
> > > 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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> >
> > -- ========================================
> >
> > 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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>
> -- ========================================
>
> 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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--
========================================
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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