[gmx-users] Problems with Energy Minimization in Solvated Ligand

Toan Nguyen toan.nguy at berkeley.edu
Sat Dec 30 03:39:46 CET 2017 

So I believe I solved my problem by changing to:
couple-intramol             = yes
in my enmin.00.mdp file.

However, looking at the gromacs manual
<http://manual.gromacs.org/online/mdp_opt.html>, changing the
couple-intramol to "yes"  means that:

"The intra-molecular Van der Waals and Coulomb interactions are also turned
on/off. This can be useful for partitioning free-energies of relatively
large molecules, where the intra-molecular non-bonded interactions might
lead to kinetically trapped vacuum conformations. The 1-4 pair interactions
are not turned off."

In your tutorial
<http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gmx-tutorials/complex/04_ions.html>,
the provided mdp file has couple-intramol = 0.
Would making the above changes affect my analysis if I intend to do an MBAR
(Multi-state Bennett Acceptance Ratio) analysis?

On Fri, Dec 29, 2017 at 2:42 PM, Justin Lemkul <jalemkul at vt.edu> wrote:

>
>
> On 12/29/17 5:14 PM, Toan Nguyen wrote:
>
>> Is it okay to see this same warning when running npt and nvt?
>>
>
> No, hence the "IMPORTANT" part of the message. Your system is unstable and
> you should diagnose why.
>
> http://www.gromacs.org/Documentation/Terminology/Blowing_Up#
> Diagnosing_an_Unstable_System
>
> -Justin
>
> "*WARNING: Listed nonbonded interaction between particles 1 and 119*
>> *at distance 2.103 which is larger than the table limit 2.000 nm.*
>>
>> *This is likely either a 1,4 interaction, or a listed interaction inside*
>> *a smaller molecule you are decoupling during a free energy calculation.*
>> *Since interactions at distances beyond the table cannot be computed,*
>> *they are skipped until they are inside the table limit again. You will*
>> *only see this message once, even if it occurs for several interactions.*
>>
>> *IMPORTANT: This should not happen in a stable simulation, so there is*
>> *probably something wrong with your system. Only change the
>> table-extension*
>> *distance in the mdp file if you are really sure that is the reason."*
>>
>> On Thu, Dec 28, 2017 at 6:38 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>
>>
>>> On 12/28/17 9:36 PM, Toan Nguyen wrote:
>>>
>>> How would we go about doing another energy minimization? I realized I
>>>> sent
>>>>
>>>> Double precision, or using conjugate gradients, or using steepest
>>> descents
>>> with a smaller initial step.
>>>
>>> the wrong tutorial earlier, I was actually following this one Absolute
>>>
>>>> Binding Free Energy - Gromacs 2016
>>>> <http://www.alchemistry.org/wiki/Absolute_Binding_Free_Energ
>>>> y_-_Gromacs_2016>
>>>> by David Mobley.
>>>>
>>>> Good luck getting that to converge with a peptide :)
>>>
>>> -Justin
>>>
>>>
>>> On Thu, Dec 28, 2017 at 6:30 PM, Justin Lemkul <jalemkul at vt.edu> wrote:
>>>
>>>>
>>>> On 12/28/17 8:40 PM, Toan Nguyen wrote:
>>>>>
>>>>> Hi,
>>>>>
>>>>>> I am currently following the Gromacs Tutorial by Bevan Lab (Link
>>>>>> <http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin/gm
>>>>>> x-tutorials/complex/05_EM.html>)
>>>>>> to run a simulation on a ligand from the 1mnb protein. However, I am
>>>>>> running into issues with the energy minimization step where I run *gmx
>>>>>> mdrun -v -nt 1 -deffnm em*, but an error arises saying,
>>>>>>
>>>>>> *"WARNING: Listed nonbonded interaction between particles 1 and 119*
>>>>>> *at distance 2.108 which is larger than the table limit 2.000 nm.*
>>>>>>
>>>>>> *This is likely either a 1,4 interaction, or a listed interaction
>>>>>> inside*
>>>>>> *a smaller molecule you are decoupling during a free energy
>>>>>> calculation.*
>>>>>> *Since interactions at distances beyond the table cannot be computed,*
>>>>>> *they are skipped until they are inside the table limit again. You
>>>>>> will*
>>>>>> *only see this message once, even if it occurs for several
>>>>>> interactions.*
>>>>>>
>>>>>> *IMPORTANT: This should not happen in a stable simulation, so there
>>>>>> is*
>>>>>> *probably something wrong with your system. Only change the
>>>>>> table-extension*
>>>>>> *distance in the mdp file if you are really sure that is the reason."*
>>>>>>
>>>>>> and then energy minimization runs for ~120 steps before saying,
>>>>>>
>>>>>> *"Energy minimization has stopped, but the forces have not converged
>>>>>> to
>>>>>> the*
>>>>>> *requested precision Fmax < 100 (which may not be possible for your
>>>>>> system).*
>>>>>> *It stopped because the algorithm tried to make a new step whose size
>>>>>> was
>>>>>> too*
>>>>>> *small, or there was no change in the energy since last step. Either
>>>>>> way,
>>>>>> we*
>>>>>> *regard the minimization as converged to within the available machine*
>>>>>> *precision, given your starting configuration and EM parameters.*
>>>>>>
>>>>>> *Double precision normally gives you higher accuracy, but this is
>>>>>> often
>>>>>> not*
>>>>>> *needed for preparing to run molecular dynamics.*
>>>>>>
>>>>>> *writing lowest energy coordinates.*
>>>>>>
>>>>>> *Steepest Descents converged to machine precision in 94 steps,*
>>>>>> *but did not reach the requested Fmax < 100.*
>>>>>> *Potential Energy  = -1.4016720e+05*
>>>>>> *Maximum force     =  1.9569155e+03 on atom 259*
>>>>>> *Norm of force     =  9.6724640e+01"*
>>>>>>
>>>>>> When I do the tutorial with the provided input files, this message
>>>>>> does
>>>>>> not
>>>>>> show up and the energy minimization reaches 500+ steps. How can I fix
>>>>>> my
>>>>>> input files so that the energy minimization does not run into the
>>>>>> problem
>>>>>> above?
>>>>>>
>>>>>> Below is the link to my input files:
>>>>>> Link
>>>>>> <https://drive.google.com/drive/folders/1a38C0lnBWi6n1IfalGU
>>>>>> -SKc0_cnxBRqa?usp=sharing>
>>>>>>
>>>>>> The messages above just indicate you probably have a bad contact
>>>>>>
>>>>> somewhere
>>>>> early on in the minimization process. If EM finishes (which it does),
>>>>> then
>>>>> the bad contact has been at least somewhat resolved. The forces are
>>>>> still
>>>>> somewhat high, so you will likely need additional minimization and/or
>>>>> double precision, as the message from mdrun suggests.
>>>>>
>>>>> The protein-ligand complex tutorial isn't really relevant here; you
>>>>> just
>>>>> have a very simple protein in water, not that it makes much difference.
>>>>> But
>>>>> don't get too hung up on having a "ligand" in your system. You have a
>>>>> peptide, so it's nothing that requires any really special procedur
>>>>> <https://maps.google.com/?q=that+requires+any+really+special
>>>>> +procedur&entry=gmail&source=g>
>>>>>
>>>>> e.
>>>>>
>>>>> -Justin
>>>>>
>>>>> --
>>>>> ==================================================
>>>>>
>>>>> Justin A. Lemkul, Ph.D.
>>>>> Assistant Professor
>>>>> Virginia Tech Department of Biochemistry
>>>>>
>>>>> 303 Engel Hall
>>>>> 340 West Campus Dr.
>>>>> Blacksburg, VA 24061
>>>>>
>>>>> jalemkul at vt.edu | (540) 231-3129
>>>>> http://www.biochem.vt.edu/people/faculty/JustinLemkul.html
>>>>>
>>>>> ==================================================
>>>>>
>>>>> --
>>>>> Gromacs Users mailing list
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>>>>>
>>>>>
>>>> --
>>> ==================================================
>>>
>>> Justin A. Lemkul, Ph.D.
>>> Assistant Professor
>>> Virginia Tech Department of Biochemistry
>>>
>>> 303 Engel Hall
>>> 340 West Campus Dr.
>>> Blacksburg, VA 24061
>>>
>>> jalemkul at vt.edu | (540) 231-3129
>>> http://www.biochem.vt.edu/people/faculty/JustinLemkul.html
>>>
>>> ==================================================
>>>
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>>
>>
> --
> ==================================================
>
> Justin A. Lemkul, Ph.D.
> Assistant Professor
> Virginia Tech Department of Biochemistry
>
> 303 Engel Hall
> 340 West Campus Dr.
> Blacksburg, VA 24061
>
> jalemkul at vt.edu | (540) 231-3129
> http://www.biochem.vt.edu/people/faculty/JustinLemkul.html
>
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>
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> Gromacs Users mailing list
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