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

Tue Apr 2 11:06:30 CEST 2019

@Peter: Please don't take it the wrong way, it was just my lame attempt at
a tongue in cheek reply to your comment.

Now, to actually contribute with something of relevance to the topic at
hand, I agree with what most users/developers have mentioned before, i.e. a
ligand binding study using mixed representation with a CG active site is
not ideal for all the above stated reasons (and more). Given that resources
are scarce, I'd give metadynamics a serious try. It has been used
successfully in the past for this type of study (we have used it in our
group for GPCRs quite recently). Funnel metadynamics, in particular, seems
like a good candidate:

https://www.pnas.org/content/110/16/6358.short

We have quite decent resources at our group and we still use metadynamics
and other enhanced sampling methods all the time. Unless you're at DE Shaw
Research, brute force atomistic MD is almost never feasible for
large/complex systems.

J

On Tue, Apr 2, 2019 at 10:49 AM Peter Kroon <p.c.kroon at rug.nl> wrote:

> @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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