Hi Ray,
thanks a lot for your offer. I will collect the data and come back to you next week.
Many thanks again,
Hannes.
________________________________________
From: Ray Luo, Ph.D. [ray.luo.uci.edu]
Sent: 28 June 2013 18:47
To: AMBER Mailing List
Cc: Wesley Smith
Subject: Re: [AMBER] Is there any major change of MMPBSA.py in AmberTools 13?
Hannes,
As pointed out by Jason, the difference is most likely due to the
different default nonpolar solvation methods between different
releases. Can you share with us your input files so we can reproduce
your observed differences? We'll be happy to share with you what we
find with your input and data files. A few snapshots will do. Please
email us off the list.
All the best,
Ray
On Fri, Jun 28, 2013 at 8:13 AM, Hannes Loeffler
<Hannes.Loeffler.stfc.ac.uk> wrote:
> 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
>>
>
> --
> Scanned by iCritical.
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
--
Scanned by iCritical.
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Sun Jun 30 2013 - 02:00:02 PDT
