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

Jianguo Li ljggmx at yahoo.com.sg
Wed Feb 23 05:25:30 CET 2011

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.


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 

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.


> Cheers
> Jianguo
> ------------------------------------------------------------------------
> *From:* Justin A. Lemkul <jalemkul at vt.edu>
> *To:* Gromacs Users' List <gmx-users at gromacs.org>
> *Sent:* Tuesday, 22 February 2011 21:10:08
> *Subject:* Re: [gmx-users] Can g_wham support using different temperature for 
>different windows?
> 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 
>  > (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 
>  > 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 
>  >
> 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 <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 11:13:05
>  > *Subject:* Re: [gmx-users] Can g_wham support using different temperature 
>for different windows?

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