[gmx-users] [gmx-user] RMSD analysis of protein-ligand complex

Thu Dec 26 18:11:28 CET 2019

Okay thank you!
*What exactly should I do to fix the topology high penalty?*
Do a DFT optimization again for the molecule and do the parametrization ?
Is there a guideline to follow?

On Thu, Dec 26, 2019 at 10:07 PM Justin Lemkul <jalemkul at vt.edu> wrote:

> On Thu, Dec 26, 2019 at 9:41 AM Quin K <profiles.ke at gmail.com> wrote:
>
> > Thank you!
> > I noted that there are two options called
> >  Guess bond orders from connectivity
> >  Include parameters that are already in CGenFF
> > In the parachem website.
> > Would checking these specially the second one would fix some of these
> > problems?
>
>
> No. Work with the topology you have. The second option also has nothing to
> do with parameter assignment and will lead to duplicate parameter errors
> later.
>
> -Justin
>
>
> > I have not used these options.
> >
> > Regards!
> >
> > On Thu, Dec 26, 2019 at 6:54 PM Justin Lemkul <jalemkul at vt.edu> wrote:
> >
> > >
> > >
> > > On 12/26/19 9:05 AM, Quin K wrote:
> > > > Thank you!
> > > > This is the output I got from parachem.
> > > >
> > >
> >
> https://docs.google.com/document/d/180rWUj4XE-_OFBCVPsJajohNRKUYIClcP_V3cOer5qw/view
> > > > Can this be used as it is?
> > > >
> > > > I used it as it is and did not validate or optimized further, could
> > that
> > > be
> > > > the reason why ligand got detached from binding site during MD
> > > simulation?
> > >
> > > Possibly. The charge and dihedral penalties are not low enough to be
> > > considered sufficient without explicit validation using QM water
> > > interaction energy and a 1-D potential energy surface around the
> > > (potentially) problematic dihedral. It may be that the topology is
> fine,
> > > but as the header says, penalties between 10-50 cannot be trusted
> > > without proving the parameters are OK.
> > >
> > > -Justin
> > >
> > > > Thanks in advance!
> > > > Regards
> > > > Q
> > > >
> > > > On Wed, Dec 18, 2019 at 1:23 PM Justin Lemkul <jalemkul at vt.edu>
> wrote:
> > > >
> > > >>
> > > >> On 12/18/19 6:40 AM, Quin K wrote:
> > > >>> I generated ligand topology using parachem website, I didn't do any
> > > >>> adjustments after, just used it as it is.
> > > >> What do the penalty scores tell you about the quality of the
> > parameters?
> > > >>
> > > >> -Justin
> > > >>
> > > >>> On Tue, 17 Dec 2019, 1:11 pm Justin Lemkul, <jalemkul at vt.edu>
> wrote:
> > > >>>
> > > >>>> On 12/15/19 1:18 PM, Quin K wrote:
> > > >>>>> Hi
> > > >>>>> Thank you!!!
> > > >>>>>
> > > >>>>> Let's say during restraining of ligand, if I increased  the -fc
> > value
> > > >> to
> > > >>>>> 10000 (i had 1000) or higher and equilibrated it for longer time
> > > like 1
> > > >>>> or
> > > >>>>> 2 ns (I had 100ps), would it help?
> > > >>>> Possibly.
> > > >>>>
> > > >>>>> Also would  restraining the protein and ligand independently
> help?
> > > >>>>> Or is generating a better ligand topology the only way to solve
> > this
> > > >>>> issue?
> > > >>>>
> > > >>>> It depends on how you validated the ligand topology. Do you have
> > > >>>> evidence that it is of sufficiently high quality?
> > > >>>>
> > > >>>> -Justin
> > > >>>>
> > > >>>>> Thanks in advance.
> > > >>>>> Regards
> > > >>>>>
> > > >>>>> On Sun, Dec 15, 2019 at 11:07 PM Justin Lemkul <jalemkul at vt.edu>
> > > >> wrote:
> > > >>>>>> On 12/15/19 11:47 AM, Quin K wrote:
> > > >>>>>>> Hi All,
> > > >>>>>>>
> > > >>>>>>> Further to following email, i just noted that the ligand has
> > > detached
> > > >>>>>> from
> > > >>>>>>> binding site.
> > > >>>>>>> Is there a way to prevent this from happening?
> > > >>>>>>> It happened to me once before with the same complex.
> > > >>>>>> If the ligand is dissociating on a time scale that it shouldn't
> > > (e.g.
> > > >>>>>> you expect it should stay bound), that suggests the ligand
> > topology
> > > is
> > > >>>>>> insufficiently accurate, arising from interactions with the
> > protein
> > > >> that
> > > >>>>>> are too weak and/or interactions with water that are too strong.
> > > >>>>>>
> > > >>>>>>> Doesn't boundary conditions prevent ligand from detaching from
> > > >> binding
> > > >>>>>> site
> > > >>>>>>> in protein during MD simulation?
> > > >>>>>> No, PBC does not do this. A periodic system contains copies of
> > > >> whatever
> > > >>>>>> is happening in the central image.
> > > >>>>>>
> > > >>>>>> -Justin
> > > >>>>>>
> > > >>>>>> --
> > > >>>>>> ==================================================
> > > >>>>>>
> > > >>>>>> Justin A. Lemkul, Ph.D.
> > > >>>>>> Assistant Professor
> > > >>>>>> Office: 301 Fralin Hall
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> > > >> --
> > > >> ==================================================
> > > >>
> > > >> 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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> > > --
> > > ==================================================
> > >
> > > 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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>
> ==========================================
>
> 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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