Hi Thomas:
Thanks. I'll make a few points, a few convincingly, the other ones as a try.
(1) I am not aware of new, wide-breath problems that do not require huge
efforts. Certainly, however, these should not be along an obviously wrong
direction.
(2) Whether or not the partial charges are appropriate for the dominant
conformation (if there is one) I know how to judge: fitting or no fitting of
the calculated dipole moment with the experimental dipole moment (which I have
measured in various media). I have thought frequently to the problem of
Boltzmann averaging and have also seen it applied to real cases in a paper in
Biochemistry.
(3) RESP charges for the molecule made in fragments could be obtained with
NWChem HF-6-31G*. I already did that for not so large molecules (unpublished,
actually I have not yet published anything done with MD. I am now in a position
not to be pressed to publish, which may also explain why I am now at these
problems). The problem is the conformation (see above), although I still have
to apply restraint from NMR. Those I have (NOE) are in organic solvents,
however and 4D NMR is not at my reach: with 3D NMR there are still unresolved
areas, even at 800MHz.
(4) My plan was to have the two key files, parameters and coordinates, for MD
and running simulated annealing in vacuum. (With NWChem I can't have the
parameters). The algorithm I have has proven remarkably efficient with a
variety of large molecules. Then calculating partial charges for the dominating
conformations and averaging. I am not aware of any other possibility, since the
degrees of freedom are too many for MM based on MMFF94 or similar ff. Perhaps,
your suggestion to give a try with guessed partial charges is to be considered
seriously. If not else because with less complicated molecules (very well
minimized) I have seen large disagreement in the distribution between the HF
6-31-G* RESP (giving a good fit with the experimental dipole moment) and the
partial charge from antechamber.
(5) The time I have spent effortless so far on the problem (two days and half,
although actually it was the machine that lost time, I was on the highlands
with my pointing breed looking for chukars) was due largely to lack of clarity
of the chapter on antechamber, as I wrote (surely coupled to naiveness from my
side). Now - if my plan above is not wrong - I am again faced by lack of
clarity in descriptions (at the moment I have no access to the original divcon
publication): that is, if "divide and conquer" requires the molecule be made of
fragments, each with its name (as in the examples presented for divcon on the
web), or the 500 atoms may be a single fragment and "divide and conquer" will
work on it. If it does not work, I can delay my doing with these problems until
there is advancements on either the theory or my thoughts.
Regards
francesco pietra
--- Thomas Cheatham III <tec3.utah.edu> wrote:
>
> > I still feel that my best chances are through divcon. I gratefully accept
> your
> > suggestion to go to divcon directly, chapter 7. Checking against QuantumBio
> web
> > pages, it seems that the version of divcon in Amber9 is the latest, 4.5.
>
> I would like to re-emphasize Professor Case's point regarding the
> sensibility of charge-fitting for large molecules... (below).
>
> > > You are really taking the charge derivation part of antchamber where it
> was
> > > not designed to go. Even it things don't crash, you would need to
> examine
> > > whether or not the charge model one gets for very large molecules is a
> good
> > > one.
> > >
> > > The "am1-bcc" charge philosophy is to perform a geometry minimization on
> the
> > > input molecule before assessing the charges. This makes sense for small
> > > molecules, where geometry optimization is fast. For large, floppy
> molecules,
> > > it probably makes much less sense. Again, this is a scientific question
> that
> > > will require patience and research. If you wish to use divcon for this
>
> It is not clear to me whether or not the charges will make *any* sense at
> all for a large molecule with AM1-BCC or RESP charges. This is a research
> question and is unknown. I would be highly skeptical regardless of how
> much computer power you throw at this with DIVCON, that is unless you
> explicitly consider conformational dependence (and exploring
> conformational dependence in a large molecule with QM quickly becomes
> prohibitive). Even then, I would have to be convinced that the resulting
> charges are better than either random, or ad hoc assigment (i.e. carbon
> slightly negative i.e. -0.2, hydrogen slightly positive +0.1,
> electronegative atoms more negative), or simpler fragment based
> approaches.
>
> An easier way to think about this is to consider the RESP charge fitting
> that AM1-BCC is intended to approximate. Essentially, you perform QM
> calculations to estimate an electrostatic potential and then find point
> charges on the atoms that best fit that potential. If the molecule is
> large (and/or floppy), the fit is necessarily noisy and will not be as
> well determined. [Bayly/Cieplak/Kollman saw this (sort of) with the
> original ESP fitting on small molecules that evolved into RESP to prevent
> buried charges from becoming large during the fit; the charges became
> large since their value did not have considerable influence on the ESP,
> i.e. they were not well determined; see RESP papers by Bayly/Cieplak.]
>
> Moreover, if a molecule is large, the resulting charges will depend
> heavily on the conformation chosen. This is why we tend to consider small
> molecules for the charge fitting in vacuum, ideally looking at explicitly
> at the conformational dependence (or choosing particular subsets of
> accessible conformations, such as extended backbones in peptides). It is
> not simply a matter of simplicity, but that the model makes sense with
> small molecules and may start to break down with larger ones.
>
> What I would recommend doing is breaking up a larger molecule into
> "pieces" and fitting each independently first (perhaps even with a RESP
> approach). Then you could spend more time sampling in molecular mechanics
> space the conformations (which is presumably what you want to do) rather
> then spending weeks generating charges for a very large molecule that may
> be unrealistic.
>
> If you do not want to do this, then I would suggest calculating the
> charges on multiple different representative conformations of the large
> molecule and average them (probably I would use R.E.D.). How many
> conformations depends on how flexible the molecule is, and averaging would
> be best in principle using some kind of Boltzmann weighting (and this is
> all a research question). Then I would compare the results to random
> charges and ad hoc / rule based charges...
>
> -- tec3 at utah
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