Thank you very much for the detailled explanation. But those
calculations do not yet include entropical contributions. I wonder if
that would not make my final dG actually positive despite a ligand
seemingly happily staying stably in its binding site.
On Fri, 28 Jun 2013 10:16:25 -0400
Jason Swails <jason.swails.gmail.com> wrote:
> On Fri, Jun 28, 2013 at 4:22 AM, Hannes Loeffler
> <Hannes.Loeffler.stfc.ac.uk
> > wrote:
>
> > I have not tested against AmberTools 12 yet but I've also got a dG
> > which seems too high. I have however checked with mm_pbsa.pl and
> > the results are totally different: DELTA TOTAL = -9.6205 vs PBTOT =
> > -47.07. The protocols are not fully compatible I suppose but I add
> > the relevant output below.
> >
> > [snip]
> >
>
>
> >
> > Differences (Complex - Receptor - Ligand):
> > Energy Component Average Std. Dev. Std.
> > Err. of Mean
> >
> > -------------------------------------------------------------------------------
> > VDWAALS -59.5492 2.3688
> > 0.3350
> > EEL -30.0831 5.7671
> > 0.8156
> > EPB 50.1463 4.3827
> > 0.6198
> > ENPOLAR -40.0096 1.0869
> > 0.1537
> > EDISPER 69.8750 1.3036
> > 0.1844
> >
> > DELTA G gas -89.6322 6.2040
> > 0.8774
> > DELTA G solv 80.0117 4.7020
> > 0.6650
> >
> > DELTA TOTAL -9.6205 4.1658
> > 0.5891
> >
> > [snip]
> >
>
>
> >
> > # DELTA
> > # -----------------------
> > # MEAN STD
> > # =======================
> > ELE -30.08 5.83
> > VDW -59.55 2.39
> > INT 0.00 0.00
> > GAS -89.63 6.27
> > PBSUR -7.65 0.18
> > PBCAL 50.22 4.44
> > PBSOL 42.57 4.40
> > PBELE 20.13 3.79
> > PBTOT -47.07 3.83
> > GBSUR -7.65 0.18
> > GB 44.45 4.00
> > GBSOL 36.80 3.96
> > GBELE 14.36 3.19
> > GBTOT -52.84 3.16
> >
>
> These results are actually not quite as different as you'd think.
> First of all, mm_pbsa.pl reports the total electrostatic energy as
> the sum of the electrostatic and the 1-4 electrostatic energies.
> MMPBSA.py, on the other hand, reports electrostatic energies as ONLY
> the electrostatic energies. The 1-4 non-bonded interactions are in
> some sense 'bonded' or 'internal' interactions in that they will
> cancel completely if a single trajectory calculation is done
> (correctly). Since this is a good way of checking for vdW and charge
> consistency between the prmtops, MMPBSA.py handles them separately
> and makes sure that they cancel completely when only a single
> trajectory is used for binding energy calculations.
>
> The size of the 1-4 EEL term is typically of the correct size
> relative to the EEL term to completely explain the discrepancy
> between mm_pbsa.pl and MMPBSA.py in the ELE/EEL terms in the complex,
> receptor, and ligand. More importantly, the DELTA EEL/ELE term is
> exactly the same between mm_pbsa.pland MMPBSA.py (a good sign). The
> only term that's slightly different is
> PBCAL/EPB, in which the binding difference is 50.15 in MMPBSA.py and
> 50.22 in mm_pbsa.pl, which is well within the accuracy of the method.
>
> The reason for the apparently huge difference between MMPBSA.py and
> mm_pbsa.pl comes entirely from the non-polar solvation term.
> MMPBSA.py allows the PB code to compute the non-polar solvation free
> energy contribution. The default scheme in PBSA is to decompose the
> non-polar part into a repulsive surface area-based term and an
> attractive dispersion-based term (ENPOLAR and EDISPER). The
> non-polar solvation free energy in MMPBSA.py computed using this
> scheme is ~29 kcal/mol. mm_pbsa.pl, on the other hand, uses the ENP
> = a*SASA + b form for the non-polar energy (which is why PBSUR and
> GBSUR are identical). Therefore, the non-polar term, which is 29
> kcal/mol in MMPBSA.py, is -7.65 kcal/mol in mm_pbsa.pl, yielding a
> ~37 kcal/mol difference in the total binding free energy JUST from
> the non-polar contribution!
>
> And this accounts for basically the full difference between
> mm_pbsa.pl and MMPBSA.py. To my knowledge, there are no plans to
> expand mm_pbsa.pl to support the non-polar solvation schemes
> implemented in PBSA.
>
> FWIW, this non-polar solvation term is responsible for almost all of
> the variation found from version to version of PBSA. The
> electrostatic solvation free energy fluctuates within 1 kcal/mol or
> so (as seen between mm_pbsa.pl and MMPBSA.py).
>
> Hope this helps,
> Jason
>
--
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Received on Fri Jun 28 2013 - 08:30:03 PDT
