RE: AMBER: QMMM to follow reaction involving water

From: Ross Walker <>
Date: Mon, 30 Jul 2007 21:49:23 -0700

Hi Bud,

> I have been doing QMMM (using a development version of Amber10
> sander furnished by Ross Walker). The basic design is steered
> QMMM with the steered coordinate along a proposed scissile C-N
> bond. I have been having a lot of trouble with this calculation
> when I incorporate close waters into the QM region. These
> problems seems to be of two kinds: (1) the QM water(s) diffuse
> away from the enzyme active site, (2) the QM calculation (SCC-DFTB
> w/o dispersion corrections) has great difficulty achieving SCF.

To follow up on what Gustavo said the issue is definately with the waters
diffusing and your QM region essentially expanding as a bubble until it gets
close to the bxo size. This occurs because of the way the direct space QM
calculation is done. For stability all MM atoms that are within the cut off
distance of ANY QM atom are included in the direct space sum for ALL QM
atoms. At present using restraints is probably the only real solution
available. An alternative would be to write some script that ran Amber for
say 100 steps, then quit, checked the restart file to find the nearest X
waters to the main QM region, wrote a new input file with a different list
of iqmatoms and then reran sander for another 100 steps and so on.

Gustavo and I ultimately plan to automate this process within the code so
that you can just run a QM simulation and have it recompute the nearest
waters on the fly. This will obviously play havoc with the energies but
should be okay for conformational analysis or to look at say proton transfer
with a water molecule. As soon as we have it implemented I'll let you know
so that you can test it.

As for the SCF convergence DFTB does sometimes have problems but it
shouldn't normally be that bad unless you give it a very bad structure - do
you see the convergence problems right from the beginning or after so much
simulation? If it is from the beginning then you could try running either
with qm_ewald and qm_pme turned off for 1000 steps or so (since convergence
is easier without this) to get you away from the initial bad structure and
then turn it back on. Alternatively you could reduce the convergence
criteria slightly to see if that helps - this causes inaccuracies with the
gradients but again can be useful if you have bad structures. You might also
want to set nstlim to 1 and then set verbosity=4 in the qmmm namelist and
take a look at the convergence process in the DFTB calculation to see if it
ever gets close to converging.

There is also as you say the potential issue with the convergence problems
being a function of the waters being a long way away. This is likely
particularly true when running with PME since you start to get weird direct
and reciprocal charge distributions and the error in the Ewald sum may be
getting large. E.g. you can get things where you have an MM water wedged in
between two QM waters.

Is it always after the waters have started to diffuse that you get the
convergence problems?

As for the restraint force for the time being I would just set it using
standard harmonic restraints and a very weak force constant - as weak as you
can get away with (<1.0?). You might want to run a full classical
equilibration first to make sure the density is good before you add
restraints. If you don't get a decent sphere of waters picked out though you
may have issues with unrestrained waters tunnelling in and out of the
restrained sphere. Ideally you'd probably want to restrain the sphere of
classical waters around the outside of the chosen QM waters to try to stop
the QM waters from escaping through the boundary rather than restraining the
QM waters themselves - this would have less of an effect on the reaction
pathway I would guess. I'm not sure how well it would work in practice
though - something to try. What you ideally want is a water cap type
restraint but keeping all the periodic boundary stuff - this would require
some major code changes though.

Good luck.

|\oss Walker

| HPC Consultant and Staff Scientist |
| San Diego Supercomputer Center |
| Tel: +1 858 822 0854 | EMail:- |
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Received on Wed Aug 01 2007 - 06:07:30 PDT
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