[gmx-users] Coarse-grained Protein-ligand simulations
Mac Kevin Braza
mebraza at up.edu.ph
Tue Apr 2 00:16:53 CEST 2019
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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