[gmx-users] FEP vs PMF

Thu Nov 24 03:15:40 CET 2016

"To which experiment quantity those PMF and FEP are comparable?"

There are experiments like isothermal calorimetry (ITC), surface plasmon
resonance (SPR) and saturation transfer difference-nuclear magnetic
resonance (STD-NMR).  You could also see if your predicted binding
affinities correlate well to the log of IC50s, EC50s or CC50s, which would
be interesting :)

Cheers,

Billy

On 24 November 2016 at 03:29, Alex <alexanderwien2k at gmail.com> wrote:

> Thanks Billy,
>
> If so, then, what do you call the what you get from only one leg of the
> thermodynamic cycle? I mean calculation of only for example bound(complex)
> state or unbound(ligand) state.
>
> How the DDG should be calculated?
>
> To which experiment quantity those PMF and FEP are comparable?
>
> Thanks,
> Cheers,
> Alex
>
> On Wed, Nov 23, 2016 at 3:52 PM, Billy Williams-Noonan <
> billy.williams-noonan at monash.edu> wrote:
>
> > Hi Alex,
> >
> > From your PMF you get a DG of binding.  From an absolute FEP calculation
> > where you close the thermodynamic cycle, you _also_ get that same DG of
> > binding.  Just because you're subtracting or adding two values to close
> the
> > cycle doesn't make it a DDG value.
> >
> > Yes you could compare both methods to experiment. :)
> >
> > Cheers,
> >
> > Billy
> >
> > On 24 November 2016 at 01:34, Alex <alexanderwien2k at gmail.com> wrote:
> >
> > > Thanks Justin.
> > >
> > > Ok, in PMF it is not DDG, but in FEP as far as I know it is DDG
> (binding
> > > free energy) when one complete the thermodynamic cycle as I have done
> > here.
> > >
> > > Then, what is the DDG in a PMF?
> > >
> > > What could be comparable between "PMF and experiment" or between "FEP
> and
> > > experiment"?
> > >
> > > Thanks.
> > >
> > > regards,
> > > Alex
> > >
> > > On Tue, Nov 22, 2016 at 9:20 PM, Justin Lemkul <jalemkul at vt.edu>
> wrote:
> > >
> > > >
> > > >
> > > > On 11/21/16 4:30 PM, Alex wrote:
> > > >
> > > >> what I have as PMF itself has been already harvested from gmx wham.
> > > >>
> > > >
> > > > This is not a DDG, it's just DG, the difference between the plateau
> > > > (unbound) and minimum (bound).  That's the value you compare with the
> > FEP
> > > > result, though I'm not clear how one obtains a reasonable and
> converged
> > > > value for the FEP in bound and unbound states.  PMF is a very
> > > > straightforward method to do this.  FEP requires lots of other
> > > restraints,
> > > > etc that have to be accounted for.
> > > >
> > > > -Justin
> > > >
> > > >
> > > > Regards
> > > >>
> > > >> On Mon, Nov 21, 2016 at 10:24 PM, Billy Williams-Noonan <
> > > >> billy.williams-noonan at monash.edu> wrote:
> > > >>
> > > >> You could also do WHAM analysis with gmx wham. :)
> > > >>>
> > > >>> On 22 November 2016 at 07:48, Alex <alexanderwien2k at gmail.com>
> > wrote:
> > > >>>
> > > >>> Yes, indeed the thermodynamic cycle is closed.
> > > >>>> If I am not wrong an integration like below should be done over
> PMF
> > in
> > > >>>> order to get adsorption energy which is equivalent to
> \Delta\Delta G
> > > in
> > > >>>> FEP.
> > > >>>>
> > > >>>> \Delta F_{ads} = -K_{B}*T Log[ Integrate(exp(-PMF/K_{B}*T)/L)]
> > > >>>>
> > > >>>> in which L is the interval where PMF starts to its plateau.
> > > >>>>
> > > >>>> Regards,
> > > >>>>
> > > >>>> Alex
> > > >>>>
> > > >>>> On Mon, Nov 21, 2016 at 9:24 PM, Billy Williams-Noonan <
> > > >>>> billy.williams-noonan at monash.edu> wrote:
> > > >>>>
> > > >>>> Assuming you have closed the thermodynamic cycle correctly (which
> no
> > > >>>>>
> > > >>>> doubt
> > > >>>>
> > > >>>>> you have), then I would think you have just measured the same
> > > quantity
> > > >>>>>
> > > >>>> with
> > > >>>>
> > > >>>>> absolute FEP as you did using PMF with umbrella sampling.  You
> have
> > > the
> > > >>>>> same dG of binding, but with different methods. :-)
> > > >>>>>
> > > >>>>> Cheers,
> > > >>>>>
> > > >>>>> Billy
> > > >>>>>
> > > >>>>> On 22 November 2016 at 07:19, Alex <alexanderwien2k at gmail.com>
> > > wrote:
> > > >>>>>
> > > >>>>> Hi Billy,
> > > >>>>>>
> > > >>>>>> Thanks for your response,  whatever you want to call it, it is
> the
> > > >>>>>> difference between the free energies of the system in bonded(or
> > > >>>>>>
> > > >>>>> complex)
> > > >>>>
> > > >>>>> and unbounded(or ligand) states, so it is [\Delta G_{bounded} -
> > > >>>>>>
> > > >>>>> \Delta
> > > >>>
> > > >>>> G_{unbounded}].
> > > >>>>>>
> > > >>>>>> Regards,
> > > >>>>>> Alex
> > > >>>>>>
> > > >>>>>> On Mon, Nov 21, 2016 at 9:06 PM, Billy Williams-Noonan <
> > > >>>>>> billy.williams-noonan at monash.edu> wrote:
> > > >>>>>>
> > > >>>>>> If you're calculating an absolute free energy of dissociation,
> why
> > > >>>>>>>
> > > >>>>>> would
> > > >>>>>
> > > >>>>>> it
> > > >>>>>>
> > > >>>>>>> be a "\Delta\Delta G"?
> > > >>>>>>>
> > > >>>>>>> Kind Regards,
> > > >>>>>>>
> > > >>>>>>> Billy
> > > >>>>>>>
> > > >>>>>>> On 22 November 2016 at 04:12, Alex <alexanderwien2k at gmail.com>
> > > >>>>>>>
> > > >>>>>> wrote:
> > > >>>>
> > > >>>>>
> > > >>>>>>> Dear gromacs user,
> > > >>>>>>>>
> > > >>>>>>>> For a reaction (dissociation of a amino acid from a solid
> > surface
> > > >>>>>>>>
> > > >>>>>>> in
> > > >>>>
> > > >>>>> aqueous solution), I have calculated the "\Delta\Delta G" by free
> > > >>>>>>>>
> > > >>>>>>> energy
> > > >>>>>>
> > > >>>>>>> perturbation method in alchemical analysis, and also for the
> same
> > > >>>>>>>>
> > > >>>>>>> reaction
> > > >>>>>>>
> > > >>>>>>>> I have calculated the PMF by umbrella sampling.
> > > >>>>>>>>
> > > >>>>>>>> I was wondering how I can compare these two results together?
> > > >>>>>>>>
> > > >>>>>>>> Thanks,
> > > >>>>>>>>
> > > >>>>>>>> Regards,
> > > >>>>>>>> Alex
> > > >>>>>>>> --
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> > > > ==================================================
> > > >
> > > > Justin A. Lemkul, Ph.D.
> > > > Ruth L. Kirschstein NRSA Postdoctoral Fellow
> > > >
> > > > Department of Pharmaceutical Sciences
> > > > School of Pharmacy
> > > > Health Sciences Facility II, Room 629
> > > > University of Maryland, Baltimore
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> > > >
> > > > jalemkul at outerbanks.umaryland.edu | (410) 706-7441
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