Dear Professor Walker,
The problem here is once NADH (the net charge=-2) is included in the
QM/MM-GBSA calculation (as shown in the *Figure c & d *here
<
https://drive.google.com/file/d/0B84zOE6DopPlLU9BVTd1SDk0aUE/view?usp=sharing>)
, the dGsolv (blue) and dGscf (green) show extreme instantaneous values
(dGscf<green> in dGbind can fluctuate really widely: -700~1000 kcal/mol
for example ). Therefore the abnormal behavior makes large and positive
dGbind (for example, dGbind = 34.37 kcal/mol. The dGbind calculated from
MM/GBSA using the same trajectories here is -30 kcal/mol). This happens in
igb=1,2,5,7,8 and all effective radii settings. On the other hand, if only
the ligand (net charge=0) or the ligand +Tyr156 (net charge=0) are assigned
as QM regions, the QM/MM-GBSA calculations are normal with converged
dGscf *(Figure
a & b)*.
Professor Monard suggests that "If the MM and the QM regions are charged,
the main component of the electrostatic QM/MM interaction is a
charge-charge interaction
whose value is the total charge of the QM region times the total charge of
the MM region divided by the distance between the two centers. If you are
"lucky", these two centers are close and the electrostatic interactions is
very large." Therefore, in order to avoid the charge-charge interaction,
we tried to systematically reduce the "qmcut" from the default 9,999A to 8
& 0 A, as shown in* Figure d-f*. However, the extremely positive and
negative dGscf (green lines) still happened, though less frequently.
The professor Monard further enlightens that "if you have 1 QM region
in the receptor (e.g.,NADH), and the ligand is QM, when you form the
complex, you have one big QM region where all molecular orbitals will be
delocalized between NADH
and the ligand. This could mean huge charge transfer and polarization
components."
In response, we run QM/MM-GBSA where the "ligand" is NADH+ligand
(qmcharge_lig=-2, qmcharge_com=-2, qmcharge_rec=0), the extreme values of
electrostatic interactions energy terms didn't happen with qmcutt=0, 8, and
9999 as shown in the *figures g-i*. However, the dGbind here is
unrealistic since the "NADH+ligand" is deemed as the "ligand". However,
this result seems to confirm the saying that the huge charge transfer and
polarization components between NADH and the ligand when the system forms
the complex.
I guess the charge settings in the above file should be correct? Could
you kindly let us know if you see any setting mistakes? If not, it seems
like including the charged NADH as part of the QM receptor and QM complex
region in the QM/MM-GBSA calculation is the cause of the extreme dGscf
values due to large charge-charge interactions between non-neutral QM and
MM regions AND huge charge transfer and polarization components between the
QM ligand and NADH regions.
Best,
Henry
On Fri, Apr 3, 2015 at 5:57 PM, Ross Walker <ross.rosswalker.co.uk> wrote:
> >
> > The conclusion here seems to go back to the original point: if both QM
> > and MM regions are non-neutral, the QM/MM calculations are problematic.
> If
> > the QM region includes NADH (net charge= -2) and the ligand, reducing the
> > qmcut even to 0 cannot solve the issue in our case. The huge charge
> > transfer and polarization components between NADH and the ligand, during
> > the complex forming stage, still creates extreme electrostatic values.
>
> Henry, what is your definition of being problematic - is the SCF not
> converging? - which means anything calculated from that is incorrect. Or is
> the QM calculation working but the ultimate GBSA binding result is coming
> out incorrect?
>
> The QM code should support running simulations with non zero charges
> (although the QM region requires an integer number of electrons). Are you
> setting the charge correctly in the QM calculation? - I could see how
> enforcing the charge to be zero but including 2 extra electrons could cause
> all sorts of problems.
>
> All the best
> Ross
>
>
>
>
> /\
> \/
> |\oss Walker
>
> ---------------------------------------------------------
> | Associate Research Professor |
> | San Diego Supercomputer Center |
> | Adjunct Associate Professor |
> | Dept. of Chemistry and Biochemistry |
> | University of California San Diego |
> | NVIDIA Fellow |
> | http://www.rosswalker.co.uk | http://www.wmd-lab.org |
> | Tel: +1 858 822 0854 | EMail:- ross.rosswalker.co.uk |
> ---------------------------------------------------------
>
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--
Pin-Chih Su (Henry Su)
Ph.D. canditate
Center for Pharmaceutical Biotechnology (MC 870)
College of Pharmacy, University of Illinois at Chicago
900 South Ashland Avenue, Room 1052
Chicago, IL 60607-7173
office 312-996-5388
fax 312-413-9303
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Received on Sun Apr 05 2015 - 18:00:04 PDT
