From: Haleh a (halehabdi_at_sabanciuniv.edu)
Date: Thu Dec 17 2015 - 05:42:15 CST
Dear all,
Thank you for the replies.
Actually, I have checked the histograms. They forward/backward runs
overlap, although not as nicely as the first paper mentioned above. They
are more similar to figure 5 of the FEP tutorial.
My mutations are divided into two categories. Some are surrounding active
site of an enzyme and are very close to a ligand. Others are solvent
exposed and far from the active site. In both cases, I have the end point
catastrophe. I will increase the number of the windows until I see
convergence.
Haleh
On Wed, Dec 16, 2015 at 8:49 PM, Gianluca Interlandi <
gianluca_at_u.washington.edu> wrote:
> Do you select BAR in the VMD ParseFEP window? Have you looked at the
> histograms for each window and do you see overlap between forward and
> backward?
>
> I don't know if it helps, I make the equilibration window as large as the
> data collection window.
>
> An important consideration is that the ideal situation for FEP is when the
> target state is a subset of the initial state. Since this is often not the
> case, the transformation is broken down into multiple windows but the
> windows need to overlap. One way to find this out is by looking at the
> histograms, as I mentioned above.
>
> Also, I am not familiar with your system. Is the mutated side chain buried
> in the protein or out in the solvent? Mutation of a side chain that samples
> a vast conformational space might be difficult to assess with FEP. You
> might want to first run a 50-100 ns simulation after mutating the side
> chain (with no FEP) to get an idea what the side chain does in the mutated
> state.
>
> The following papers might be helpful to you:
>
> http://www.ncbi.nlm.nih.gov/pubmed/22978683
> (in particular supporting information)
>
> http://www.ncbi.nlm.nih.gov/pubmed/14634991
>
> Gianluca
>
>
> On Wed, 16 Dec 2015, Brian Radak wrote:
>
> My guess is that your first thought is correct - the simulations are not
>> long enough.
>>
>> I would recommend:
>>
>> 1) assessing the statistical error (I'm not really familiar with
>> ParseFEP, so I don't
>> know if it does this already)
>>
>> and/or
>>
>> 2) trying another analysis method (such as a multistate technique)
>>
>> HTH,
>> Brian
>>
>> On 12/15/2015 09:59 AM, Haleh a wrote:
>> Dear NAMD users,
>> I have been trying to calculate free energy changes upon a mutation in a
>> protein via FEP method. The transformations were subdivided into 32
>> windows.
>> Each stratum consisted of 100,000 data-collection steps preceded by 25,000
>> equilibration steps.
>> For a few of my mutations the free energy change upon forward and
>> backward
>> transformations were not the same. An example of a Parsefep file for dG
>> column
>> is given below:
>>
>> fw bw
>> 0.0000 19.2024
>> 7.8597 27.3887
>> 15.8585 35.4349
>> 23.8350 42.7734
>> 30.9869 49.8046
>> 38.1433 56.4785
>> 45.1326 63.2339
>> 51.5564 69.8128
>> 57.9795 75.7305
>> 64.2681 81.6443
>> 70.2732 86.9015
>> 76.0547 91.6371
>> 81.0941 95.7292
>> 85.2021 99.6043
>> 88.3743 103.2919
>> 91.4066 106.3001
>> 93.3668 108.3961
>> 91.4244 106.6218
>> 89.3347 104.5966
>> 87.0627 101.5024
>> 84.6330 97.8175
>> 81.7766 93.0725
>> 78.8473 88.2228
>> 75.5645 83.1926
>> 70.4596 77.7998
>> 65.0760 71.9186
>> 59.6825 65.5346
>> 54.1291 59.0037
>> 48.5446 52.6676
>> 42.7863 45.8779
>> 36.9261 38.9123
>> 31.0231 31.7249
>> 25.1445 25.1445
>>
>>
>> I tried running the simulation with longer data collection and
>> equilibration
>> time but it did not help. Does anyone have any idea why such a problem
>> exist
>> and how to solve it?
>>
>> Many thanks,
>> Haleh Abdizadeh
>>
>>
>> --
>> Brian Radak
>> Postdoctoral Appointee
>> Leadership Computing Facility
>> Argonne National Laboratory
>>
>> 9700 South Cass Avenue, Bldg. 240
>> Argonne, IL 60439-4854
>> (630) 252-8643
>> brian.radak_at_anl.gov
>>
>>
>>
> -----------------------------------------------------
> Gianluca Interlandi, PhD gianluca_at_u.washington.edu
> +1 (206) 685 4435
> http://artemide.bioeng.washington.edu/
>
> Research Assistant Professor at the Department of Bioengineering
> at the University of Washington, Seattle WA U.S.A.
> -----------------------------------------------------
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