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

Billy Williams-Noonan billy.williams-noonan at monash.edu
Sat Dec 30 04:30:43 CET 2017


Hi Toan,

There is probably either something wrong with your topology or the initial
geometry of your system is somehow wrong.  How did you paramaterise your
system?

Cheers,

Billy

On 30 December 2017 at 12:39, Toan Nguyen <toan.nguy at berkeley.edu> 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?
>
> 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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> >>>>> /Mailing_Lists/GMX-Users_List before posting!
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> >>>>> send a mail to gmx-users-request at gromacs.org.
> >>>>>
> >>>>>
> >>>>>
> >>>> --
> >>> ==================================================
> >>>
> >>> 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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