[gmx-users] Can g_wham support using different temperature for different windows?
Justin A. Lemkul
jalemkul at vt.edu
Tue Feb 22 04:13:05 CET 2011
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>
> *To:* Gromacs Users' List <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>>
> > *To:* Discussion list for GROMACS users <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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