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

Sat Dec 30 17:18:07 CET 2017

On 12/29/17 9:39 PM, Toan Nguyen wrote:
> 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?

Possibly, though I've never dealt with a peptide like you are. What do 
you find people do in the literature? (De)coupling intramolecular 
interactions does affect sampling, quite dramatically.

-Justin

> 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
>>>>>>
>>>>>> ==================================================
>>>>>>
>>>>>> --
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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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>>>> 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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>> 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

==================================================