[gmx-users] ligand moving out during umbrella sampling

Thu May 11 07:32:35 CEST 2017

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

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.

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*