You can use center of mass restraints (either via nmropt or nfe COLVAR
module) to restrain the ligand in the binding pocket.
I do not know how the COLVAR method gets factored in, if at all, into the
energy terms. From experience, it does not seem to show up under the
restraint term in the output file. However, the nmr opt restraint energy
does get reported there. I do not know if this means it will also be
included in the MMPB/MMGB output, you would have to run a test to see. In
either case, however, you can easily caluclate the restraint energy based
on the center of mass distances in the trajectory, or in the appropriate
restraint / colvar output file (if you specify one in the input setting)
On Wed, Jan 30, 2019 at 10:24 AM Sundar <jubilantsundar.gmail.com> wrote:
> Thanks for your reply.
> While steered MD with work calculations is a good option for a few
> protein-ligand complexes, it may become computationally prohibitive as I
> will be performing the same calculations for a few hundred complexes. I'm
> sort of bound to end-point free energy calculations.
>
> Key questions that still stay unanswered are
> 1. Can I loosely restrain the ligand in the binding pocket during the
> simulation and do MMPBSA calculation?
> 2. Will the ligand restrain energy be taken into account in MMPBSA
> calculation?
>
> Thanks,
> Sundar
>
> On Mon, Jan 28, 2019 at 7:53 AM Josh Berryman <
> the.real.josh.berryman.gmail.com> wrote:
>
> > For my 2 cents I'd just like to mention that while PBSA is sometimes
> quoted
> > as a reference for training GBSA models, in fact GBSA methods are often
> > more stable and handier, as they have no grid, and have more free
> > parameters for tuning to commonly-encountered cases (like a druglike in a
> > protein binding pocket).
> >
> > For flexible or loosely bound systems you will need to make some sort of
> > entropy measurement, you might want to think about umbrella sampling,
> > thermodynamic integration or steered molecular dynamics (all of which
> work
> > with explicit solvent (better) as well as implicit). Implemented methods
> > abound, however none are computationally cheap. If you have access to
> GPU
> > accelerators then just using TI or steered MD to pull the drug in and out
> > of the pocket a few times is quite a neat and not-so-slow way to measure
> > the work.
> >
> > Josh
> >
> >
> >
> >
> >
> >
> > On Mon, 28 Jan 2019 at 13:54, David A Case <david.case.rutgers.edu>
> wrote:
> >
> > > On Sat, Jan 26, 2019, Sundar wrote:
> > > >
> > > >I am performing MMPBSA and MMGBSA calculations for a protein-ligand
> > > >complex. Protein is small, containing 50 residues. GBSA is giving a
> > Delta
> > > >Total of -5.2 and PBSA is giving 0.34 kcal/mol. How to interpret the
> > > >difference between these numbers? Why's GBSA binding affinity is
> > stronger
> > > >than PBSA?
> > >
> > > This is not an unusual difference. You might read various reviews on
> > > MM/PB(GB)SA end point methods. It is in general much harder to get
> > > useful quantitative results than many new users expect.
> > >
> > > >
> > > >How long should be the simulation to get reliable results? How do I
> > > measure
> > > >the convergence?
> > > >Do multiple replicates of the simulation help to improve the accuracy?
> > > >
> > > >What if the ligand leaves the binding site during the simulation? Can
> I
> > > >include those frames as well in these binding affinity calculations?
> If
> > > >not, can I use some restraints to keep the protein-ligand bound
> > together?
> > >
> > > Above are good questions, but not ones that can be easily answered on a
> > > mailing list, since there probably are no general answers. Don't be
> > > afraid to experiment. If you ligand is not stable in the binding site,
> > > then the assumption that you can correctly sample configurations from
> > > the end-point "bound" state is probably not valid.
> > >
> > > ....dac
> > >
> > >
> > > _______________________________________________
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> > > AMBER.ambermd.org
> > > http://lists.ambermd.org/mailman/listinfo/amber
> > >
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> >
>
>
> --
> Thanks,
> Sundar Thangapandian
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Received on Wed Jan 30 2019 - 11:00:03 PST
