Re: [AMBER] Distorted and Failed Phosphate Simulations

From: Sigurd Friis Truelsen <sigut.env.dtu.dk>
Date: Tue, 24 Nov 2015 10:08:00 +0000

Hi again,

Thank you all for your valuable input. I have made some tests based on your suggestions, where I increased the angle force constants as suggested by Karl and David. I am not particularly concerned about the phosphate conformations during the MD simulation as I will use QMMM in this case, but I would like to avoid QM in order to increase my sampling. So I am looking for solutions to do this. Also I am mostly interested in the HPO4(2-) anion.

When increasing the angle force constants (with 15 kcal/mol rad2) I get the following results:
The H2PO4(-) in the protein complex completes without any errors, and it looks fine in the trajectory. However it is not the case for HPO4(2-) (which you also pointed out is less stable). I tested for 1 and 2 fs time steps.

The 1 fs time step is able to complete the minimization, heating and equilibration, but during the heating the phosphate is distorted as it interacts with a Na+ counterions which is in close proximity. The hydrogen-free oxygens orient toward the Na+ ion and the OH group points away. To me this seems like a charge interaction issue. I think it is necessary to have charge neutrality in the system, but only to get a stable simulation. When I build the system in leap, the counterions are placed just next to the phosphate, and I don't know if I should move them and stop including them?

The 2 fs time step is suddenly distorted during the equilibration, where the hydrogen is attracted towards one of the other oxygens and the simulation stops due to a shake error. This could be a van der Waals interaction problem that Pavel suggested, as the hydrogen is unprotected. I have used the gaff.dat hydroxyl group, which should have a VDW radius of 1.008 if I understand the parameter file correctly. If this is the standard HO atom with insufficient VDW radius, which HO atom could I use, or would it require a full parametrization?

To summarize, I have two questions. 1) What would you suggest to do with the counterion/phosphate interaction? 2) Which HO group would be suitable to use and how should this be done. Would this require a full parametrization of the phosphate?

Thanks in advance
Sigurd Friis Truelsen
________________________________________
Fra: Karl Kirschner [k.n.kirschner.gmail.com]
Sendt: 20. november 2015 10:36
Til: AMBER Mailing List
Emne: Re: [AMBER] Distorted and Failed Phosphate Simulations

Hello again,

I had some time and took a detailed look at HF/6-31G(d)'s H2PO4(-) most
stable conformation. I performed constraint optimization for all of the
unique bond, angles, and the ho-oh-p5-oh torsions at HF/6-31G(d) (132
calculations total) to generate potential energy curves for each. Charges
were computed to be balanced with Amber's protein residues. Following
Dave's suggestion, if I increase the each of the angle constants that are
listed in GAFF by 15 kcal/mol rad^2 (+10 kcal/mol rad^2 to each was
sufficient) to the following values, then I am able to perform all of the
equivalent MM optimization (i.e. none of them erroneously stop):

ho-oh-p5 70.88 110.14
o -p5-o 61.01 115.80
o -p5-oh 58.79 115.26
oh-p5-oh 59.58 102.45

However, the resulting MM curves are not in good agreement with the
HF/6-31G(d) target values, as can be seen by the two attached
representative figures that are labeled according to antechamber's assigned
atom types. Both the energies and the geometries are not in good agreement.
The MM angle curve is a discontinuous curve since the ho-oh-p5-oh torsion
changes as the angle bends (the QM is a continuous curve). One could argue
that the QM theory level is not good enough to model H2PO4(-), but I think
it is good enough to illustrate that this system will require careful
parameterization if you are concerned about its conformations during MD
simulations.

I also modified the ho atom type's Lennard-Jones parameters to those of
Glycam06j (i.e. ho: 0.2000 0.0300), but was unable to perform many of the
MM optimization while using the default GAFF angles parameters.

Bests,
Karl

On Thu, Nov 19, 2015 at 2:26 PM, David A Case <david.case.rutgers.edu>
wrote:

> On Thu, Nov 19, 2015, Sigurd Friis Truelsen wrote:
> >
> > I have problems running regular MD simulations with inorganic
> > phosphate HPO4(2-), H3PO4(-) and H3PO4 .
>
> A "typical" problem with protonated phosphates is that a hydrogen can be
> attracted to a neighboring oxygen on the same phosphate, and there is no
> Lennard-Jones term on the hydrogen to prevent it from collapsing onto the
> oxygen. I'm not sure whether this is the cause of your problems or not,
> but
> you should monitor MD or minimzation carefully to look for such
> interactions.
>
> Although it is a kludge, it generally works to increase the O--P--O and
> P--O--H angle force constants to enforce a conventional geometry about the
> phorphorus and prevent such intramolecular H--O interactions from ocurring.
> Take a look at the frcmod.phosaa10 file (in $AMBEHROME/dat/leap/parm),
> which
> has parameters we use for phosphorylated amino acids, along with comments
> about how the angle parameters were determined. A similar strategy is
> likely
> to work for phosphate itself.
>
> ...dac
>
>
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>



--
Karl. N. Kirschner, Ph.D.
Research Associate
Bonn-Rhein-Sieg University of Applied Sciences
Grantham-Allee 20, 54757 Sankt Augustin, Germany
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Received on Tue Nov 24 2015 - 02:30:03 PST
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