[gmx-users] ligand moving out during umbrella sampling
Justin Lemkul
jalemkul at vt.edu
Thu May 11 17:33:40 CEST 2017
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
>>>>>> 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
>>>
>>> ==================================================
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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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