I don't have a problem, per se, but would like to discuss the problems
that may, or may not, arise when mixing force fields.
It is clear to me why one would not want to calculate the free energy
of binding for two proteins, one using the amber ff and the other
using the opls ff; also it is clear that there would be problems
simulating a box of water half of which is tip3p and half of which is
spc. The common thing to these examples is that such simulations would
apply dissimilar parameter sets for similar functional groups and
therefore any results could be subject to significant biases, the
source of which will not be obvious to the user.
However, If one was simulating the binding of a protein to DNA, or a
protein embedded in a lipid bilayer, the functional groups are no
longer shared by different types of macromolecules. Since I work on
membrane proteins, let me take the case of an oplsaa protein in a
Berger lipid bilayer. Not only are these ff's differently generated,
but one is all-atom and one is united-atom. The important difference
in this case is that there are few functional groups of the lipids
that resemble those of the protein e.g. the NH3 of a lipid head-group
choline and a lysine of the protein. Generally though, the functional
groups are entirely different between these macromolecules. I believe
that this is also the case for protein-DNA simulations. Therefore,
what biases can possibly occur by the combination of different ff's in
this case that could not also occur by combinations that exclusively
use a single ff?
I take the extreme example and ask: what special relevance do the opls
ion parameters have to the opls protein parameters? It seems to me
that, although they "derive them in a manner consistent with how the
rest of the force field was originally derived"
(http://wiki.gromacs.org/index.php/Parameterization), in this extreme
case I believe that this is an entirely abstract concept of no
particular value. In other words, how can Na+ possibly be generated
consistently/inconsistently with an amino acid that contains no Na?
To clearly state my current point of view in the absence of a shred of
data, I suggest the following: "One should not combine parameters that
are derived inconsistently of one another except in cases where such
combination can be made without introducing multiple parametric
definitions of a given functional group." If you believe that, it
would therefore be acceptable to combine the following in any way: i)
protein, ii) water, iii) ion, iv) DNA, v) lipid, vi) carbohydrate. The
seventh group: small molecules, is difficult to classify since one
must take into consideration the specific functional groups. For
example, I would suggest that ATP and a protein should be fine if
different ff's are used, but that ATP and DNA should use a consistent
ff when simulated in conjunction.
As we ramp up our simulations for ever-increasing cpu power and for
gromacs 4, these questions are well beyond pedantic. It is one thing
to develop parameters for a small molecule consistently with the the
methodology used for the protein/DNA ff. However, simulations of more
than one different type of macromolecule (e.g. protein-DNA
simulations) would greatly benefit, it seems, from the ability to use
the DNA parameters that lead to the most accurate sampling of DNA
phase space and the protein parameters that lead to the most accurate
sampling of protein phase space. It is my conjecture that such
combinations would not only be appropriate, but that they would be
optimal.
Disclaimer: If you are considering combining differently-generated
force-fields, please do not take this post as encouragement. The
standard logic never to combine force-fields is still recommended. I
only wanted to have some discussion on this topic.
Thanks for all comments, especially those that are in disagreement
with my proposition.
Chris.
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