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

Tue Apr 2 05:18:27 CEST 2019

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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