Matthias,
This calls for a MMPBSA calculation by hand. You can get all the
energies for the complex, the receptor, and the ligand, and compute all
the averages by Excel, for example, to see whether the MMPBSA outputs
are correct.
All the best,
Ray
==========================================
Ray Luo, Ph.D.
Associate Professor in Computational
Biochemistry and Molecular Biophysics
Dept of Molecular Biology and Biochemistry
Dept of Biomedical Engineering
University of California, Irvine, CA 92697-3900
Email: rluo.uci.edu Phones: (949) 824-9528, 9562
Web: http://rayl0.bio.uci.edu/rayl/
==========================================
Matthias Negri wrote:
> Hi Ray,
> no I am following a single trajectory approach.. this is why my
> results sounds so confusing to me.
>
> However, I calculated the surface area for some snapshots and the
> average value is about 950 A^2, thus a congruent value.
>
> Interestingly, when I visualize prmtop and coordinate of the
> "receptor" (protein and cofactor) with VMD the structure looks fine,
> no distorted bonds, correct lengths, etc. Otherwise, when I visualize
> prmtop and coordinate with Sirius, a carbon atom of the cofactor seems
> to be far away.
> This does not happen for the complex.
>
> What can the reason be for it? Might this be related with the strange
> values emerged from the MM-PBSA calculation?
>
> Best regards,
>
> Matthias
>
>
> Ray Luo, Ph.D. ha scritto:
>> Matthias,
>>
>> Here are my observations of your numbers and related thoughts:
>>
>> 1) It seems that you are using the multiple trajectory approach, i.e.
>> one
>> separate trajectory for each of complex, receptor, and ligand?
>> Otherwise, I
>> don't understand the large INT energy in the Delta G part ...
>>
>> 2) The ELE energy, i.e. gas-phase Coulombic energy, and the PBELE
>> energy are
>> both small and almost cancel out each other. This is an indication
>> that the
>> electrostatic component seems to behave reasonably well in the
>> calculation.
>>
>> 3) The PBSUR energy of -5 kcal/mol indicats a surface burial of 1000 A^2
>> upon binding if you are using a surface tension of 5 cal/mol-A^2.
>> This seems
>> to be consistent with the very negative VDW energy upon binding. Can you
>> rationalize the number for the surface burial upon binding, i.e. by
>> doing a
>> VMD visualization or some independent surface area calculation for a
>> single
>> snapshot to see whether the order of magnitude is correct?
>>
>> Good luck!
>> Ray
>>
>> On Wed, May 5, 2010 at 4:45 PM, Matthias Negri
>> <m.negri.mx.uni-saarland.de>wrote:
>>
>>
>>> Hi,
>>> many thanks for the suggestion. I will check again the charges of my
>>> system
>>> as well as the protonation states. In fact the "receptor" includes as
>>> cofactor NADPH, which has a net charge of -4, mostly delocalized on the
>>> phosphote oxygens.
>>>
>>> Again, thanks for the hint
>>>
>>> Matthias
>>>
>>> Dwight McGee ha scritto:
>>>
>>> Hi,
>>>
>>>> In my experiences I have only seen cases where the DELTA G was
>>>> very high
>>>> when certain things such as the ligand or residues from the
>>>> receptor which
>>>> interact w/ the ligand were not protonated correctly. As a
>>>> suggestion I
>>>> would make absolutely certain that everything has the correct
>>>> charge. Good
>>>> luck
>>>>
>>>> On Wed, May 5, 2010 at 6:17 AM, Matthias Negri
>>>> <m.negri.mx.uni-saarland.de>wrote:
>>>>
>>>>
>>>>
>>>>
>>>>> Hello to everyone,
>>>>> I'm experiencing some problems in an MM-PBSA calculation. My system
>>>>> consists of enzyme, cofactor (NADPH) and inhibitor. Previous
>>>>> calculations
>>>>> (on different enzyme conformers) run fine, while for this specific
>>>>> case
>>>>> the
>>>>> final delta PBTOT I obtained is way to large (-324.94), mostly due
>>>>> to an
>>>>> imbalanced delta GAS (-356.32; in particular my delta INT is
>>>>> -120.87 and
>>>>> delta VdW is -216.83). The topology files and the crd of complex,
>>>>> receptor
>>>>> and ligand look nice when I visualize them in VMD), no bonds are
>>>>> distorted
>>>>> or broken, etc.
>>>>>
>>>>> Hereafter my output file of the MM-PBSA calculation:
>>>>>
>>>>> # COMPLEX RECEPTOR
>>>>> LIGAND
>>>>> # ----------------------- -----------------------
>>>>> -----------------------
>>>>> # MEAN STD MEAN STD
>>>>> MEAN
>>>>> STD
>>>>> # ======================= =======================
>>>>> =======================
>>>>> ELE -7236.85 96.82 -7192.48 96.10
>>>>> -25.76
>>>>> 0.48
>>>>> VDW -1199.12 28.96 -993.70 30.53
>>>>> 11.41
>>>>> 1.22
>>>>> INT 5792.37 46.59 5882.25 51.16
>>>>> 30.99
>>>>> 3.65
>>>>> GAS -2643.60 103.44 -2303.93 106.04
>>>>> 16.64
>>>>> 3.53
>>>>> PBSUR 104.29 1.24 105.77 1.26
>>>>> 3.44
>>>>> 0.02
>>>>> PBCAL -3415.05 88.12 -3424.16 88.17
>>>>> -27.19
>>>>> 0.51
>>>>> PBSOL -3310.76 87.43 -3318.39 87.45
>>>>> -23.75
>>>>> 0.51
>>>>> PBELE -10651.91 32.14 -10616.63 32.91
>>>>> -52.95
>>>>> 0.58
>>>>> PBTOT -5954.37 44.68 -5622.32 51.50
>>>>> -7.11
>>>>> 3.48
>>>>>
>>>>> # DELTA # -----------------------
>>>>> # MEAN STD
>>>>> # =======================
>>>>> ELE -18.62 6.32
>>>>> VDW -216.83 5.70
>>>>> INT -120.87 16.97
>>>>> GAS -356.32 17.62
>>>>> PBSUR -4.92 0.17
>>>>> PBCAL 36.30 4.20
>>>>> PBSOL 31.38 4.23
>>>>> PBELE 17.68 5.12
>>>>> PBTOT -324.94 17.04
>>>>>
>>>>> What can the reason for such huge energy differences be? Where
>>>>> should I
>>>>> search for the mistake (If any is in)?
>>>>>
>>>>> Attached you can find input, output for the mm-pbsa calculation,
>>>>> as well
>>>>> as
>>>>> prmtop and crd of ligand, "receptor (protein and cofactor)" and
>>>>> complex.
>>>>>
>>>>> Many thanks,
>>>>>
>>>>> Matthias Negri
>>>>>
>>>>> _______________________________________________
>>>>> 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
>>>
>>>
>>>
>> _______________________________________________
>> 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
>
_______________________________________________
AMBER mailing list
AMBER.ambermd.org
http://lists.ambermd.org/mailman/listinfo/amber
Received on Thu May 06 2010 - 15:00:03 PDT
