Dear Professor Monard,
The QM charges are different because the ligand is neutral (
qmcharge_lig=0). If we include NADH (net charge=-2) into the QM region,
the net charge of the QM region in complex and the receptor will be -2
(qmcharge_com=-2, qmcharge_rec=-2).
Interestingly, as you suggested, if 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 or 8, as shown in the plots here
<
https://drive.google.com/file/d/0B84zOE6DopPlMGY4ZFBkU1phY2M/view?usp=sharing>.
However, the dGbind here is unrealistic since the "NADH+ligand" is deemed
as the "ligand".
However, this result seems to confirm your saying that the huge charge
transfer and polarization components between NADH and the ligand when the
system forms the complex.
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.
Best,
Henry
On Thu, Apr 2, 2015 at 3:42 AM, Gerald Monard <
Gerald.Monard.univ-lorraine.fr> wrote:
> Dear Henry,
>
> Just checking your input file below: why are the QM charges different in
> your input file? I would guess that qmcharge_lig = qmcharge_com =
> qmcharge_rec. Does this mean that the QM region is different between
> ligand/complex/receptor systems?
> Let me be more clear: 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.
> If you run QM/MM-GB/SA where the "ligand" is NADH+your current ligand
> (i.e., no QM region in the receptor, only the "ligand"), do you still
> have your problem?
>
> Gerald.
>
> On 04/02/2015 09:27 AM, psu4.uic.edu wrote:
> > Dear Professor Monard,
> >
> > Thanks for the detailed response. This is very interesting.
> >
> > I find the Amber default qmcut in QM/MM-GBSA in MMPBSA.py (The
> cutoff
> > for the qm/mm charge interactions.) is 9,999 A, which is an usually large
> > value. We assume adjust the qmcut value into a smaller value and ignore
> > some longer range electrostatic interactions between non-neutral QM and
> MM
> > regions might help. Therefore, we set the qmcut as 8A because all the
> > charged amino acids in the MM region are at least 11A away from the
> > non-neutral QM region in the in-house crystal structure. However, in
> > the situation that qmcut = 8 and QM & MM regions both contain net
> charges,
> > we still can see large electrostatic interactions. This might be because
> > the charged amino acids in the MM region at some points, might be less
> than
> > 8A away from the QM region in the MD trajectories.
> >
> > However, if we further test qmcut = 0 ( QM and MM regions both
> contain
> > net charges), the large electrostatic interactions in QM/MM-GBSA still
> > happens, though significantly less frequent. This confuses us, since
> > qmcut=0 should mute the charge-charge interactions and make dipole-dipole
> > interactions as the major component. Our guess is that even though
> > dipole-dipole interactions are less, but still susceptible, to
> distances.
> > Therefore, in qmcut=0, as long as both QM and MM regions are non-neutral
> > and the distances of these two regions are close enough, the large
> > electrostatic interactions from dipole-dipole interactions might still
> > happen (though less frequently)? Thanks in advance for enlightening.
> >
> > Best,
> > Henry
> >
> > On Fri, Mar 27, 2015 at 3:27 AM, Gerald Monard <
> > Gerald.Monard.univ-lorraine.fr> wrote:
> >
> >> Hi,
> >>
> >> What you see is something very general for QM/MM calculations, although
> >> I'm not aware of any papers discussing it: you should avoid a
> >> non-neutral QM region, especially in the case of a charged MM region.
> >> It comes from the QM/MM electrostatic interactions. The point charges of
> >> the MM part polarizes the QM part. You can think of your MM point charge
> >> set in terms of a multipolar development at the center of the MM region
> >> (total charge + dipole + quadrupole + etc.). You can do the same for the
> >> QM region. 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.
> >>
> >> In your case, when you use a trajectory, these centers move along the
> >> trajectory. This will yield large changes if the two centers are close.
> >>
> >> If your MM part and the QM part are neutral, then the main interaction
> >> component is a dipole-dipole interaction that is less susceptible to the
> >> distance.
> >>
> >> If you want to verify my saying, check the total charge of the MM part,
> >> and make it neutral if it is not.
> >> You can also turn the MM charges off and check the differences in ESCF.
> >> I would guess that the numbers will change a lot in the case the QM part
> >> is charged.
> >>
> >> My two cents,
> >>
> >> Gerald.
> >>
> >>
> >> On 03/24/2015 06:06 PM, psu4.uic.edu wrote:
> >>> Dear Amber,
> >>>
> >>>
> >>> We have used a series of protein-ligand binding trajectories to
> test
> >>> MM/PBSA, MM/GBSA and QM-MM/GBSA extensively. However, if we include
> >> NADH,
> >>> which has net charges equal to -2, into the QM region, EGB and ESCF
> (QM d
> >>> Gelectro) don’t converge in some of the test cases (ESCF in dGbind can
> >>> fluctuate really widely: -700~100 kcal/mol for example ). Therefore the
> >>> abnormal behavior makes large and positive dGbind (for example, dGbind
> =
> >>> 34.37 kcal/mol. For example, 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
> >>> various effective radii settings.
> >>>
> >>>
> >>> However, if the net charge is equal to 0 in the QM-MM region
> (NADH
> >> not
> >>> included), QM-MM/GBSA can offer converged and high agreements with
> >>> experimental data as MM/PBSA and MM/GBSA do, across various igb and
> >> effective
> >>> radii setting. Could any guru enlighten? The following is an example
> >> of
> >>> QM-MM/GBSA input, which includes the NADH cofactor (residue 101) and
> the
> >>> ligand (residue 100). Therefore, the net charges of QM regions in both
> >>> complex and receptor are -2 since the ligand doesn't have any charge.
> >>>
> >>>
> >>> The test is performed in AmberTools13/ the latest bug fix 26 and
> >>> Amber12/the
> >>> latest bug fix 26.
> >>>
> >>>
> >>> &general
> >>>
> >>> keep_files=2,interval=10,
> >>>
> >>> /
> >>>
> >>> &gb
> >>>
> >>> igb=8,
> >>>
> >>> saltcon=0.100,
> >>>
> >>> ifqnt=1,
> >>>
> >>> qmcharge_lig=0,
> >>>
> >>> qmcharge_com=-2,
> >>>
> >>> qmcharge_rec=-2,
> >>>
> >>> qm_residues=100,101,
> >>>
> >>> qm_theory='PM3',
> >>>
> >>> /
> >>>
> >>> Best,
> >>>
> >>> Henry
> >>> _______________________________________________
> >>> AMBER mailing list
> >>> AMBER.ambermd.org
> >>> http://lists.ambermd.org/mailman/listinfo/amber
> >>>
> >>
> >> --
> >>
> >>
> ____________________________________________________________________________
> >>
> >> Prof. Gerald MONARD
> >> SRSMC, Université de Lorraine, CNRS
> >> Boulevard des Aiguillettes B.P. 70239
> >> F-54506 Vandoeuvre-les-Nancy, FRANCE
> >>
> >> e-mail : Gerald.Monard.univ-lorraine.fr
> >> tel. : +33 (0)383.684.381
> >> fax : +33 (0)383.684.371
> >> web : http://www.monard.info
> >>
> >>
> >>
> ____________________________________________________________________________
> >>
> >>
> >> _______________________________________________
> >> AMBER mailing list
> >> AMBER.ambermd.org
> >> http://lists.ambermd.org/mailman/listinfo/amber
> >>
> >
> >
> >
>
> --
>
> ____________________________________________________________________________
>
> Prof. Gerald MONARD
> SRSMC, Université de Lorraine, CNRS
> Boulevard des Aiguillettes B.P. 70239
> F-54506 Vandoeuvre-les-Nancy, FRANCE
>
> e-mail : Gerald.Monard.univ-lorraine.fr
> tel. : +33 (0)383.684.381
> fax : +33 (0)383.684.371
> web : http://www.monard.info
>
>
> ____________________________________________________________________________
>
>
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> http://lists.ambermd.org/mailman/listinfo/amber
>
--
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 Fri Apr 03 2015 - 16:00:02 PDT
