[gmx-users] ligand moving out during umbrella sampling

abhisek Mondal abhisek.mndl at gmail.com
Mon May 15 08:45:48 CEST 2017


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.





> -Justin
>
>
>>> I have choose my reaction coordinate to be along -Z axis and want to
>>> apply
>>> biasing potential accordingly with restraining the ligand movement. Can
>>> you
>>> please suggest where am I failing with this code ?
>>>
>>> Thank you.
>>>
>>>
>>>
>>> On Tue, May 9, 2017 at 1:11 AM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>>
>>>
>>>>
>>>> On 5/8/17 10:00 AM, abhisek Mondal wrote:
>>>>
>>>> On Sun, May 7, 2017 at 11:37 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>>>>
>>>>>
>>>>>
>>>>>> On 5/7/17 1:57 AM, abhisek Mondal wrote:
>>>>>>
>>>>>> Hi,
>>>>>>
>>>>>>>
>>>>>>> For your ease of understanding regarding what is happening during
>>>>>>> this
>>>>>>> above said umbrella-mdrun, I have shared the trajectory video file
>>>>>>> the
>>>>>>> following link.
>>>>>>> https://drive.google.com/drive/folders/0B6O-L5Y7BiGJQ1FIc2tIRFE2dE0
>>>>>>>
>>>>>>> Is this normal given that the mdp code being used ? I basically have
>>>>>>> no
>>>>>>> idea with this step, so please help me out. I'm using gromacs-4.6.2.
>>>>>>>
>>>>>>>
>>>>>>> Your setup is incorrect.  You're applying a biasing potential only
>>>>>>>
>>>>>> along
>>>>>> z, so the ligand can move freely along x and y.  A protein-ligand
>>>>>> complex
>>>>>> has spherical symmetry, so you should set the reaction coordinate to
>>>>>> the
>>>>>> vector connecting the ligand with some suitable subset of interacting
>>>>>> protein residues.
>>>>>>
>>>>>>
>>>>>
>>>>> I don't get it.
>>>>> We are trying not to move our configuration (generated after pulling
>>>>> simulation) along the reaction coordinate, so for restraining we are
>>>>> supposed to set pull_rate1=0.0.
>>>>>
>>>>>
>>>> Of course.  But you said set pull_k = 0 which does not make sense.  The
>>>> pulling rate *is* zero during umbrella sampling (no net displacement,
>>>> restrain to the specified distance along the reaction coordinate) and
>>>> pulling force constant should be non-zero.
>>>>
>>>> If applying biasing potential only along z is causing movement along x
>>>> and
>>>>
>>>>> y then what if we apply the biasing potential along x,y,z ? Will it
>>>>> cause
>>>>> any good in restraining the ligand?
>>>>>
>>>>>
>>>>> This is how it should be done.  The reaction coordinate should be
>>>> suitably defined based on the geometry of the system.  As I suggested
>>>> before, choose some representative residues in the active site as one
>>>> group
>>>> and the ligand as the other.  Thus defines the reaction coordinate
>>>> without
>>>> any presupposition of anything being aligned with a Cartesian axis,
>>>> which
>>>> is rarely the case.
>>>>
>>>> Moreover, you said previously "A protein-ligand complex has spherical
>>>>
>>>>> symmetry, so you should set the reaction coordinate to the vector
>>>>> connecting the ligand with some suitable subset of interacting protein
>>>>> residues.". It is really unclear to me, could you please give me some
>>>>> examples to understand it more simply? I had pulled the ligand along -z
>>>>> axis, doesn't it mean that the reaction coordinate is to be that way ?
>>>>> The
>>>>> fact that I'm struggling with is to restrain the pull configurations
>>>>> for
>>>>> further sampling.
>>>>>
>>>>>
>>>>> The reaction coordinate is whatever you define it to be.  Whether or
>>>> not
>>>> pulling along the z-axis makes sense depends on the orientation of the
>>>> system and the intrinsic geometry.  In your case, it doesn't make sense.
>>>> In my case (the tutorial, the unidirectional growth of an amyloid
>>>> fibril)
>>>> it does make sense to use a single Cartesian axis for the SMD portion
>>>> and
>>>> subsequent umbrella sampling.
>>>>
>>>> I'm really a beginner, so maybe I'm asking stupid questions. Please give
>>>>
>>>>> me
>>>>> some advise. I'm really unable to decipher the scenario in comparison
>>>>> to
>>>>> your amyloid article in JPCB.
>>>>>
>>>>>
>>>>> You should read the article to understand why I did what I did in the
>>>> tutorial, and then move on to reading articles that are more similar to
>>>> your case.  These will be much more relevant to what you're doing.
>>>>
>>>> -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
>>>>
>>>> ==================================================
>>>> --
>>>> 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*
>>>
>>>
>>
>>
>>
> --
> ==================================================
>
> 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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