Hi Mac Kevin E. Braza,
Would it be possible to use a GPU? If can manage with single precision
and need less than 8Gb of memory, a gaming GPU might give some
performance improvement.
Regards,
Benson
On 4/2/19 11:46 AM, Peter Kroon 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 <[email protected]> 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 <[email protected]>
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 <[email protected]> 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: [email protected]
Cc: [email protected]
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 <[email protected]> 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 <[email protected]>
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 <[email protected]>
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
[email protected] | (540) 231-3129
http://www.thelemkullab.com
==================================================
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