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

Tue Feb 22 04:00:00 CET 2011

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?

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. 

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 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.

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>
> *To:* Discussion list for GROMACS users <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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