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

Tue Apr 2 10:46:43 CEST 2019

@Joao: I didn't mean to imply in any way that everyone has (or should
have) a couple hundred nodes at their beck and call. Although it would
be nice. I underestimated the size of the GPCR complex, as well as how
slow atomistic simulations are :)

Now that I've tried to pull my foot out of my mouth again, back on
topic: although Martini can do (almost) anything, I am rather skeptical
of CG docking/binding studies because of the reasons I outlined earlier.
In addition, in Martini the error in the entropic term (due to a lack of
conformational freedom) in the free energy equation is compensated in
the enthalpic term. However, in a confined environment (protein pocket!)
this compensation may have to be different --- and the ligand was
parametrised in solution.

Peter

On 02-04-19 05:18, Billy Williams-Noonan wrote:
> Have you considered accelerated MD?  Like metadynamics.  Plumed has a lot
> of options there
>
> Cheers,
> Billy
>
> On Tue, 2 Apr 2019 at 09:18, Mac Kevin Braza <mebraza at up.edu.ph> wrote:
>
>> Hello Sir Benson,
>>
>> We are using Supermicro SYS-1028R-WC1R Server with 2 x 2.2Ghz 12-Core Intel
>> Processors
>> (4 x 8GB DDR4) with a single node only. Ideally, to reach the microsecond
>> simulation of GPCR-membrane
>> simulation in all-atom, we will be needing a computer cluster with at least
>> 200 parallel nodes system.
>> But even with a 50-100 parallel nodes, we will reach the simulation time
>> for a month, although we know that this is
>> challenging for us here in the Philippines.
>>
>> The specialized super-computer cluster Anton is an example of hardware that
>> have reached more than 100 microseconds
>> simulation of the all-atom GPCR-membrane simulation in a month of total CPU
>> time. It has 512 processing nodes.
>>
>> Best regards,
>> Mac Kevin E. Braza
>>
>> On Tue, Apr 2, 2019, 12:40 AM Benson Muite <benson_muite at emailplus.org>
>> wrote:
>>
>>> 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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>