[gmx-users] Coarse-grained Protein-ligand simulations

Mon Apr 1 18:39:40 CEST 2019

Hi Mac Kevin E. Braza,

What hardware are you using? What kind of hardware would be needed to do 
a full simulation instead of a coarse-grained one?

Regards,

Benson

On 4/1/19 6:49 PM, João Henriques wrote:
> GPCR + membrane systems are notoriously big systems to work with for most
> research groups, regardless of your location on the map. Even in
> "privileged Europe" many research groups would struggle to produce
> microsecond long atomistic simulations of this system within a short period
> of time. Moreover, "privileged Europe" is also home to significant computer
> resource discrepancies among its member countries. This is actually one of
> the main reasons why your group's CG model is so popular :)
>
> On Mon, Apr 1, 2019 at 5:09 PM P C Kroon <p.c.kroon at rug.nl> wrote:
>
>> Hi,
>>
>> I work in privileged Europe, so it’s good for me to get a reality check
>> once every while. Thanks.
>>
>> Coarse graining molecules for Martini is not too hard. There should be
>> some tutorials on cgmartini.nl that should help you get underway. You
>> will, however, run into the problems I mentioned, and you will need to do
>> extensive validation on the topologies of your ligands. Again, it depends
>> on your exact research question: if you’re doing high-throughput like
>> screening, qualitative models might be good enough. Also see T Bereau’s
>> automartini.
>>
>> Peter
>>
>> From: Mac Kevin Braza
>> Sent: 01 April 2019 16:06
>> To: gmx-users at gromacs.org
>> Cc: gromacs.org_gmx-users at maillist.sys.kth.se
>> Subject: Re: [gmx-users] Coarse-grained Protein-ligand simulations
>>
>> Dear Sir Peter Kroon,
>>
>> We are currently maximizing the computer capabilities to reach microsecond,
>> but to reach 1 microsecond in our lab, it would take me at least 6 months
>> to finish all one microsecond.
>> We do not have that high level capacities here in the Philippines to reach
>> it. Membrane proteins are
>> typically longer, with all the lipid bilayers, solvent, and ions present on
>> top of the protein.
>> We will need more powerful computers in this part.
>>
>> I found few works from literature on the protein-ligand representation in
>> Coarse-grained.
>> We found several papers but they are either have vague methodology in
>> describing the ligand coarse-graining method and/or not necessarily have
>> the same research problem
>> as we want to explore.
>>
>> All in all, we will finish the simulation in all-atom as long as we can,
>> and still be hopeful with
>> the coarse-graining method. What we explored as in the present is the
>> CHARMM-GUI Martini Maker,
>> yet they do not include the drug ligands in representing them in
>> coarse-grained. I still have to search for other means
>> to do this. Thank you very much!
>>
>> Best regards,
>> Mac Kevin E. Braza
>>
>> On Mon, Apr 1, 2019 at 5:59 PM Peter Kroon <p.c.kroon at rug.nl> wrote:
>>
>>> Hi,
>>>
>>> that's probably a tough cookie. My first instinct would be to just apply
>>> a more hardware, and do it all atomistically. A microsecond should be
>>> within reach. Whether it's enough is a separate matter. The problem is
>>> that most CG representations don't get the shape of both your pocket and
>>> ligand exactly right, producing unreliable answers. In addition, in most
>>> CG FFs hydrogen bonds are isotropic and not specific enough for this
>>> kind of problem.
>>>
>>> If "more hardware" is not an option you'll need to dive into literature
>>> to see if people did CG protein-ligand binding/docking/unbinding
>>> (depening on research question). I would also be very skeptical of any
>>> (absolute) kinetics produced by CG simulations.
>>>
>>> As a last ditch effort you could look into multiscaling, but that's a
>>> research topic in its own.
>>>
>>>
>>> Peter
>>>
>>>
>>> On 01-04-19 11:49, Mac Kevin Braza wrote:
>>>> Thank you Prof. Lemkul,
>>>>
>>>> I appreciate your comment on this part.
>>>>
>>>> Sir Peter Kroon,
>>>>
>>>> We want to do the coarse-grained MD simulation to access long timescale
>>>> events of the
>>>> effect of the ligand binding to the GPCR, at least microsecond . For
>> now,
>>>> the most accessible means for us is to
>>>> do the CGMD. But we are currently being cornered in choosing which
>> set-up
>>>> will best suit, and
>>>> if it will allow us to see these events. We are looking also in the
>>>> possibility of coarse-graining
>>>> the ligand, and if you can share your expertise in coarse-graining also
>>> the
>>>> ligand that would be great.
>>>> I appreciate this Sir Kroon, thank you very much!
>>>>
>>>> Best regards,
>>>> Mac Kevin E. Braza
>>>>
>>>> On Mon, Apr 1, 2019 at 5:07 PM Peter Kroon <p.c.kroon at rug.nl> wrote:
>>>>
>>>>> If I may chip in: It really depends on what you're studying, and what
>>>>> forcefield you're using to do it. Unfortunately there is no FF that
>>>>> reproduces all behaviour accurately. The art is in picking one that
>> (at
>>>>> least) reproduces what you're interested in.
>>>>>
>>>>>
>>>>> Peter
>>>>>
>>>>> On 29-03-19 17:26, Justin Lemkul wrote:
>>>>>> On 3/29/19 9:17 AM, Mac Kevin Braza wrote:
>>>>>>> Thank you Professor Lemkul,
>>>>>>>
>>>>>>> But would you suggest on how can I coarse-grained the ligand I am
>>>>>>> using? I
>>>>>>> have been searching resources online but they do not work in our
>> part.
>>>>>> I don't work with CG simulations, so I'm not much help. I would think
>>>>>> that a CG parametrization of a ligand would remove all the detail
>>>>>> you'd normally want to see in terms of ligand-protein interactions.
>>>>>>
>>>>>> -Justin
>>>>>>
>>>>>>> I hope you can help us. Thank you Prof. Lemkul!
>>>>>>>
>>>>>>> Best regards,
>>>>>>> Mac Kevin E. Braza
>>>>>>>
>>>>>>> On Fri, Mar 29, 2019, 8:59 PM Justin Lemkul <jalemkul at vt.edu>
>> wrote:
>>>>>>>> On 3/29/19 3:32 AM, Mac Kevin Braza wrote:
>>>>>>>>> Hello everyone,
>>>>>>>>>
>>>>>>>>> I am simulating a coarse-grained model of a membrane protein
>> (GPCR)
>>> in
>>>>>>>>> lipid bilayer and an all-atom ligand octopamine. I build the
>>> protein,
>>>>>>>>> solutes, and membrane in the web server CHARMM-GUI. While, I added
>>> the
>>>>>>>>> ligand to the protein complex manually using the same coordinates
>>>>>>>>> of the
>>>>>>>>> coarse-grained protein model.
>>>>>>>>>
>>>>>>>>> I used the GROMACS input files from the output of CHARMM-GUI to
>>>>>>>>> simulate
>>>>>>>>> the system. I include the LIGAND.ITP (from the PRODRG Server) to
>> the
>>>>>>>>> system.top and added the atom indexes in the index.ndx file.
>>>>>>>> Don't do this. An atomistic representation of a ligand and a CG
>>>>>>>> representation of everything else is incompatible. Mixing and
>>> matching
>>>>>>>> force fields is never a good idea. Moreover, PRODRG produces
>>> topologies
>>>>>>>> that are known to be unsuitable for MD simulations.
>>>>>>>>
>>>>>>>>> However, when I proceed with the second part of equilibration, the
>>>>>>>>> following errors occurred.
>>>>>>>>>
>>>>>>>>> *Command line*:
>>>>>>>>>      gmx grompp -f step6.2_equilibration.mdp -o
>>>>>>>>> step6.2_equilibration.tpr
>>>>>>>> -c
>>>>>>>>> step6.1_equilibration.gro -p system.top -n index.ndx
>>>>>>>>>
>>>>>>>>> Setting the LD random seed to 1722366284
>>>>>>>>> Generated 2391 of the 4656 non-bonded parameter combinations
>>>>>>>>> Excluding 1 bonded neighbours molecule type 'PROA_P'
>>>>>>>>> Excluding 1 bonded neighbours molecule type 'POPC'
>>>>>>>>> Excluding 1 bonded neighbours molecule type 'W'
>>>>>>>>> Excluding 1 bonded neighbours molecule type 'NA'
>>>>>>>>> Excluding 1 bonded neighbours molecule type 'CL'
>>>>>>>>> Excluding 3 bonded neighbours molecule type 'LIG'
>>>>>>>>> Velocities were taken from a Maxwell distribution at 303.15 K
>>>>>>>>> Removing all charge groups because cutoff-scheme=Verlet
>>>>>>>>>
>>>>>>>>> -------------------------------------------------------
>>>>>>>>> Program gmx grompp, VERSION 5.1.4
>>>>>>>>> Source code file:
>>>>>>>>> /home/gromacs-5.1.4/src/gromacs/gmxpreprocess/readir.c,
>>>>>>>>> line: 2690
>>>>>>>>>
>>>>>>>>> Fatal error:
>>>>>>>>> 20 atoms are not part of any of the T-Coupling groups
>>>>>>>>> For more information and tips for troubleshooting, please check
>> the
>>>>>>>> GROMACS
>>>>>>>>> website at http://www.gromacs.org/Documentation/Errors
>>>>>>>>> -------------------------------------------------------
>>>>>>>>>
>>>>>>>>> The 20 atoms described the ligand I placed inside the
>>> protein-membrane
>>>>>>>>> complex. I want to know if where can this error originate and how
>>>>>>>>> can we
>>>>>>>>> fix them?
>>>>>>>> This simply means you haven't specified the ligand anywhere in
>>> tc-grps.
>>>>>>>> But again, back up and reevaluate your approach, which is far more
>>>>>>>> problematic than this simple index group issue.
>>>>>>>>
>>>>>>>> -Justin
>>>>>>>>
>>>>>>>> --
>>>>>>>> ==================================================
>>>>>>>>
>>>>>>>> Justin A. Lemkul, Ph.D.
>>>>>>>> Assistant Professor
>>>>>>>> Office: 301 Fralin Hall
>>>>>>>> Lab: 303 Engel Hall
>>>>>>>>
>>>>>>>> Virginia Tech Department of Biochemistry
>>>>>>>> 340 West Campus Dr.
>>>>>>>> Blacksburg, VA 24061
>>>>>>>>
>>>>>>>> jalemkul at vt.edu | (540) 231-3129
>>>>>>>> http://www.thelemkullab.com
>>>>>>>>
>>>>>>>> ==================================================
>>>>>>>>
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