# [gmx-users] ligand moving out during umbrella sampling

Justin Lemkul jalemkul at vt.edu
Thu May 11 19:27:52 CEST 2017

On 5/11/17 1:25 PM, abhisek Mondal wrote:
> Alright. I'm trying as per your advice. Actually my system is pretty big
> and due to constraint of computation power it is taking me more time to
> test vector setup. I really appreciate your time. Thanks a lot for your
> suggestions.
>
> One thing I'm worried about here. In previous mail, I mentioned the
> "distance at start" and "ref at t=0" is negative. What does the negative
> value signify, I mean how can distance be negative ? Is is due to my poorly
> given vector definition or something else ?
>

It's a vector quantity.  It can be positive or negative depending on how you
define the groups and what their positions are.  And you're telling grompp to
pull along the negative-z dimension.

-Justin

> 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.
>>
>> -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
>>>>>>>>
>>>>>>>> Is this normal given that the mdp code being used ? I basically have
>>>>>>>> no
>>>>>>>>
>>>>>>>>
>>>>>>>> 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
>>
>> ==================================================
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>> Gromacs Users mailing list
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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

==================================================