[gmx-users] Can g_wham support using different temperature for different windows?

Jianguo Li ljggmx at yahoo.com.sg
Wed Feb 23 14:42:02 CET 2011

Thanks for your comments, Patric.

You are right. The energy barrier is too high for charged groups to translocate 
the hydrophobic region of the membrane. And my peptide contains 12 positively 
charge residues (ARG and LYS), therefore it is unlikely to sample those 
translocation. I am considering to extend my simulations to microsecond level or 
longer or use REMD.


From: Patrick Fuchs <patrick.fuchs at univ-paris-diderot.fr>
To: Discussion list for GROMACS users <gmx-users at gromacs.org>
Sent: Wednesday, 23 February 2011 19:04:05
Subject: Re: [gmx-users] Can g_wham support using different temperature for 
different windows?

I think your PMF is asymetric because your peptide is asymetric and you don't 
sample enough. To get a symetric PMF, your peptide would have to sample all the 
possible conformations *and* orientations in each window. Thus it means that for 
the windows in the center of the bilayer (where you say it's extended and 
interacts with the two monolayers) it'll have to rotate completely the other way 
round. This event will probably be *very* rare because you have to translocate 
positive charges across the membrane which cost ~ 40 to 50 kJ/mol (see the PMF 
of Lys+ and Arg+ in 10.1021/ct700324x).
So as suggested by Chris, Justin and Xavier, you'll have to sample way more than 
100 ns per window. I think you should go at least to the microsecond time scale 
(or more?). Or maybe starting from different initial conformations/orientations 
for a given window and then concatenate the different trajectories?
Also consider the remark of Xavier, TM or interfacial peptides are most of the 
time alpha-helical within the membrane. So far in literature, PMFs of a whole 
peptide across a bilayer were done by restraining the peptide in a helical 
conformation (e.g. 10.1016/j.bpj.2010.12.3682). It is anyway a very difficult 
problem (and probably impossible at atomistic resolution) to get a converged PMF 
for a whole peptide (e.g. 10.1016/j.bpj.2009.03.059).


Le 23/02/2011 05:25, Jianguo Li a écrit :
> Sorry, why do you think the PMF should be asymmetric?
> I pulled my peptide from d=9nm (above the membrane) to d=-3nm (below the
> membrane) and I did windowed umbrella sampling in the range of d=-1.05nm
> to d=9nm. At least the PMF should be symmetric with respect of the
> bilayer center in the range of d=[-1.05nm 1.05nm], something like a
> guassian distribution. But I got asymmetric PMF in this region. I also
> did reverse pulling starting from the peptide below the membrane ending
> with the peptide above the membrane. And the subsequent PMF of reversed
> pulling is also asymmetic.
> I have position restrains of the phosphate beads of the lipids in
> z-direction. So the membrane should be stable in REMD. But as you
> mentioned, if peptide is truly "stuck" in this orientation, REMD may be
> not useful. I will do a single simulation first at a higher temperature
> (e.g., 400K) in those bad windows to see if the peptide conformations
> are fully sampled.
> Cheers,
> Jianguo
> ------------------------------------------------------------------------
> *From:* Justin A. Lemkul <jalemkul at vt.edu>
> *To:* Gromacs Users' List <gmx-users at gromacs.org>
> *Sent:* Wednesday, 23 February 2011 10:24:46
> *Subject:* Re: [gmx-users] Can g_wham support using different
> temperature for different windows?
> Jianguo Li wrote:
>  > Thank you, Justin.
>  > Actually I did windowed umbrella simulations from d=-1.05nm to d=9nm.
> Since I think there is no problem in the region out of the membrane, so
> I only show the configurations within the membrane. My objective is to
> access the free energy barrier of the peptide translocate the negatively
> charged membrane. The problem is that the PMF is not symmetric with
> respect to the bilayer center due to the unconverged simulations.
> I would argue that the PMF is not symmetric because your reaction
> coordinate is not symmetric. How can you calculate a free energy of
> crossing a charged membrane when your peptide does not cross the
> membrane? What I proposed earlier was to obtain configurations at equal
> distances "above" and "below" the membrane (arbitrary in a periodic
> system, but hopefully you get the idea). If you can extract the peptide
> to the point where it is liberated from the membrane in the negative
> direction, I'd suspect you could solve your problem.
>  > Since g_wham does not support different temperatures in different
> windows, to increase the converges, I will probably consider to do REMD
> in those bad windows.
>  >
> This technique might work, provided you don't destabilize the membrane,
> but if the peptide is truly "stuck" in this orientation, I doubt that
> limited-range REMD would be very useful.

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