[gmx-users] ligand moving out during umbrella sampling

abhisek Mondal abhisek.mndl at gmail.com
Fri May 19 11:56:49 CEST 2017


On Thu, May 18, 2017 at 6:48 PM, Justin Lemkul <jalemkul at vt.edu> wrote:

>
>
> On 5/17/17 8:55 AM, abhisek Mondal wrote:
>
>> This time I think I got ligand restrained successfully during the umbrella
>> sampling. I have removed the restrain from protein, as per your advice.
>> Defined the COM vector in md_umbrella.mdp, applied pull_k1=1000 and used
>> pull_rate1=0.0.
>> I have uploaded the trajectory movie (and other mdp files) in the
>> following
>> link:
>> https://drive.google.com/drive/folders/0B6O-L5Y7BiGJQ1FIc2tIRFE2dE0
>>
>> However, I'm facing a problem. Due to the withdrawal of the position
>> restrain of protein. The protein and ligand (together) is moving around
>> the
>> box and resulting in "Distance of pull group 1 (10.441990 nm) is larger
>> than 0.49 times the box size (10.646989)" error.
>>
>> As per the video I have uploaded, if I assume this approach worked, then
>> how can I avoid this error ? Is  there any way to make sure the
>> protein-ligand remains in the middle of the box (or nearby). I have taken
>> pretty large box compared to the protein structure from the beginning.
>>
>> Please suggest me a way out.
>>
>>
> Use a larger box or use direction-periodic geometry.


 For the sake of computational power I'm leaning towards direction-periodic
geometry. However, from the mailing list entries I found out that pressure
coupling should not be used for this kind of geometry setup.
NVT coupling with no velocity generation is what I'm opting for. There are
a lot of doubt regarding the md_umbrella.mdp setup using NVT protocol.
Would you please suggest if the code (
https://drive.google.com/drive/folders/0B6O-L5Y7BiGJQ1FIc2tIRFE2dE0) looks
sensible ?

Eagerly waiting for your opinion.



>
> -Justin
>
>
> On Mon, May 15, 2017 at 5:48 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>
>>
>>>
>>> On 5/15/17 2:45 AM, abhisek Mondal wrote:
>>>
>>> On Thu, May 11, 2017 at 9:03 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>>>
>>>>
>>>>
>>>>> On 5/11/17 9:21 AM, abhisek Mondal wrote:
>>>>>
>>>>> On Thu, May 11, 2017 at 11:02 AM, abhisek Mondal <
>>>>> abhisek.mndl at gmail.com
>>>>>
>>>>>>
>>>>>>> wrote:
>>>>>>
>>>>>> Hi,
>>>>>>
>>>>>>
>>>>>>> Thank you for the explanation. It really cleared some concepts. But
>>>>>>> I'm
>>>>>>> still having my ligand moving in this step. I have modified the code
>>>>>>> as:
>>>>>>> ; Pull code
>>>>>>> pull                    = umbrella
>>>>>>> pull_ngroups            = 1
>>>>>>> pull_group0             = Protein_chain_A
>>>>>>> pull_group1             = ACO
>>>>>>> pull_geometry           = direction ; simple distance increase
>>>>>>> pull_dim           = Y Y Y         ; not to allow ligand move along
>>>>>>> other
>>>>>>> dir
>>>>>>> pull_rate1         = 0.0
>>>>>>> pull_k1           = 1000           ; kJ mol^-1 nm^-2
>>>>>>> pull_start       = yes           ; define initial COM distance > 0
>>>>>>> pull_vec1               = 0 0 -1
>>>>>>>
>>>>>>>
>>>>>>> Note that with "direction" geometry, only pull_vec1 is acting.
>>>>>>>
>>>>>> pull_dim
>>>>> is ignored.
>>>>>
>>>>> The ligand was previously moving along x,y direction when I was using
>>>>>
>>>>> pull_dim  = N N Y. So I changed it to Y in all direction and provided 0
>>>>>>
>>>>>>> as
>>>>>>> vector  and pull_rate1=0.0, so that it does not move much. But at the
>>>>>>> end
>>>>>>> of a 10ns run, I see that the ligand is still moving as it was
>>>>>>> earlier.
>>>>>>>
>>>>>>> It shows me:
>>>>>>>
>>>>>>>  Pull group  natoms  pbc atom  distance at start     reference at t=0
>>>>>>        0      1132    936665
>>>>>>        1        59      1618  -1.555                -1.555
>>>>>> Is it ok withe negative value ? Anyway this setup is not working.
>>>>>>
>>>>>>
>>>>>> Again you're trying to just apply the restraint to one dimension and
>>>>>> it
>>>>>>
>>>>> looks to be fairly arbitrary.  I already suggested using the vector
>>>>> connecting the ligand COM with the binding site residues' COM and using
>>>>> that as pull_vec1.  Draw it out.  It makes a lot more sense than trying
>>>>> to
>>>>> restrain only along one axis, which as I have said before, makes no
>>>>> sense
>>>>> in this case.
>>>>>
>>>>> Thank you for such detailed suggestion.
>>>>>
>>>>> I followed on as per your suggestion. Calculated COM of protein and
>>>> Ligand.
>>>> Calculated protein-lig vector (using COM) to be used for pulling (as
>>>> pull_vec1).
>>>> Pulling also achieved successfully.
>>>> But after pulling, when I performed the brief npt_umbrella run with
>>>> pull_rate1=0, I found the ligand is moving little bit. Could not
>>>> understand
>>>> what I have mistaken this time.
>>>> So I moved on for umbrella sampling mdrun step, with pull_rate1=0 and
>>>> pull_vec1=as determined from COM calculations. Despite I found that the
>>>> ligand is moving vigorously and got pulled away probably.
>>>> I'm putting npt_umbrella.mdp,md_umbrella.mdp,conf140.gro(used for
>>>> npt_umbrella), npt140.gro,md_umbrella run video in the following link:
>>>> https://drive.google.com/drive/folders/0B6O-L5Y7BiGJQ1FIc2tIRFE2dE0
>>>>
>>>>
>>>> Am I still missing some drastic steps ? Please suggest me if I do. I'm
>>>> totally lost here in this regard.
>>>>
>>>>
>>>> Again, don't restrain the protein.  I've said this multiple times.
>>>
>>> The pull setup looks reasonable.  Maybe you just need a stronger force
>>> constant, or you should not use the COM of the whole protein, instead the
>>> COM of a few important residues (use an index group with gmx traj -ox
>>> -com
>>> to get its coordinates).  If the specified vector is off, so too will be
>>> the resulting biasing potential.
>>>
>>> -Justin
>>>
>>> --
>>> ==================================================
>>>
>>> Justin A. Lemkul, Ph.D.
>>> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>>>
>>> Department of Pharmaceutical Sciences
>>> School of Pharmacy
>>> Health Sciences Facility II, Room 629
>>> University of Maryland, Baltimore
>>> 20 Penn St.
>>> Baltimore, MD 21201
>>>
>>> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
>>> http://mackerell.umaryland.edu/~jalemkul
>>>
>>> ==================================================
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>>>
>>
>>
>>
> --
> ==================================================
>
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 629
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
>
> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul
>
> ==================================================
> --
> Gromacs Users mailing list
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-- 
Abhisek Mondal

*Senior Research Fellow*

*Structural Biology and Bioinformatics Division*
*CSIR-Indian Institute of Chemical Biology*

*Kolkata 700032*

*INDIA*


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