[gmx-users] ligand moving out during umbrella sampling

Mon May 22 12:43:19 CEST 2017

On 5/22/17 4:04 AM, abhisek Mondal wrote:
> I have used active site residues COM for this time with Ligand COM. As a
> test case. r 6-10 | r 78-80 | r 56 | r 63 | r 35 gave me my custom group of
> residues belonging to active site. Using both the COMs now I calculated the
> vector PL (protein-ligand) and applied as pull-coord1-vec.
> However, I hate to say, after 500-600ps md_umbrella run the ligand got out
> of the active site again. It is becoming very painful.
> As you asked lastly, due to flexible ligand scenario. I'm further thinking
> not to use ligand COM, despite coordinate of some atoms near the ring
> structure. However, I'm totally confused regarding whether this approach
> will work out. Giving it a try though.
>

If your ligand is large and flexible or the protein rotates very quickly, then 
it will be hard to define the reaction coordinate in the manner that we've been 
trying.  You may have to move to something more generic like distance geometry 
with pull_dim = Y Y Y and a very large box (obviously computationally expensive) 
or you'll have to calculate the binding free energy another way entirely 
(alchemical transformation, MM/PBSA, etc).

-Justin

>
>
> On Sun, May 21, 2017 at 8:39 PM, abhisek Mondal <abhisek.mndl at gmail.com>
> wrote:
>
>> Beg your pardon, I have not ignored your comment entirely regarding using
>> specific residue COM. I just recently succeeded performing md_umbrella
>> simulation (using protein COM) on few configurations.
>> .
>> I have not used specific residues COM so far as because of some confusions
>> regrading defining it. The residue stretch is not continuous e.g. residue
>> 6-10, 78-80, 56, 63, 35 are to be active site residue. I got no idea how to
>> define such discrete set of residues using make_ndx command.
>>
>>
>>
>> On Sun, May 21, 2017 at 8:13 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>
>>>
>>>
>>> On 5/21/17 9:47 AM, abhisek Mondal wrote:
>>>
>>>> I did try the code successfully on a configuration generated after
>>>> pulling.
>>>> The NVT approach with direction-periodic geometry worked nicely for the
>>>> particular configuration.
>>>>
>>>> However, when I tried to reapply the same code (with modified COMs and
>>>> thus
>>>> pull_vec) on a different configuration, something awkward happened. The
>>>> ligand got pulled through protein and got stuck inside it. I have put the
>>>> trajectory movie alongwith md_umbrella.mdp file here:
>>>> https://drive.google.com/drive/folders/0B6O-L5Y7BiGJQ1FIc2tIRFE2dE0
>>>>
>>>> Would you please care to give some advise regarding this odd behavior.
>>>>
>>>>
>>> Likely some elements of your setup are inadequate.  You have a large,
>>> flexible ligand, so perhaps using its overall COM is inappropriate.  You're
>>> also using the entire protein COM as the other end of the reaction
>>> coordinate, and perhaps that's not good enough (I've suggested a number of
>>> times to be judicious in the choice of residues taken as the group
>>> corresponding to the protein, but it seems you're simply not doing that so
>>> I'll stop suggesting it).  Perhaps your pull vector is calculated
>>> incorrectly.  A lot going on.  Back up and do something simpler, a test
>>> case that is easy to define so you can get comfortable with setting these
>>> things up and understanding/diagnosing weird behavior.
>>>
>>> -Justin
>>>
>>>
>>> Thank you.
>>>>
>>>> On Fri, May 19, 2017 at 5:18 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>>>
>>>>
>>>>>
>>>>> On 5/19/17 5:56 AM, abhisek Mondal wrote:
>>>>>
>>>>> 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.
>>>>>>
>>>>>>
>>>>>> Try it and see what happens.
>>>>>
>>>>> -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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>>>>>
>>>>
>>>>
>>>>
>>> --
>>> ==================================================
>>>
>>> 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

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