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

Mon Apr 1 11:58:53 CEST 2019

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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