Subject: Re: CCL:Question concerning Spartan molecular modeling software

From: Gary Breton <[email-masked]>
Date: Tue, 27 Feb 2001 12:52:05 -0500

Thanks to all that responded to my question concerning the molecular
mechanics FF in PC SpartanPro.  I received many responses that corroborated
my finding that when utilizing MMFF94 (as contained within Spartan), the
chlorine in chlorocyclohexane is found to be more stable in the axial
position rather than the equatorial position (contrary to experimental
findings, and the general rule that substituents prefer the equatorial
position in order to eliminate 1,3-diaxial interactions present in the axial
position).  I also received a response from Wavefunction which some of you
may be interested in.  I have summarized the responses since a few who
responded asked me to do so.

I should note:  I carried out the same type of calculation utilizing
methylcyclohexane instead of chlorocyclohexane and DID obtain the expected
result (apparently MMFF94 being parametized for this application).  Also,
when I performed an ab initio 3-21G* calculation on the MM minimized
structures of the axial and equatorial chair conformers of
chlorocyclohexane, I DID obtain the expected result.  It would appear
therefore (to this beginner) that the safest route would be to utilize
MMFF94 to obtain starting geometries for ab initio (or maybe semi-empirical
or DFT) energy calculations rather than to read too much into the "steric"
energies provided by MMFF94.

Again, thanks for your help and best regards!

Gary Breton
Berry College

************************************************************

Wavefunction's response:

It appears like MMFF94 does not correctly predict the known energy
difference.  My guess is MMFF94 has the Cl-H 1-4 term repulsive (positive
energy), in
both conformations.  In going from the axial two of the 1-4/Cl-H contacts
are
replaced by two 1-5 repulsive terms.  And the weight of the 1-5 contact is
smaller than expected.  More likely the weight of the 1-4 term is too high,
but in most 1-4
cases the is partly canceled by a 1-4 torsion term.
    In general the VdW parameters are the hardest to fit using mechanics
method.
(Usually MP2 level is considered good.)  For one, the functional form 6-12,
7-14-buffered, exp-6 etc. are very crude approximations.   And the
parameterization
depends  highly on the parametizing method.  In Halgren's MMFF94 he put
priority on:

  1) Geometry
  2) intra-molecular torsion term's and conformation
  3) the near part of the VdW term (thus his buffered 7-14 VdW term).

To this effect MMFF has a very highly tuned torsional profile which does
as good as I know for conformations on a broad range of molecules.
(Until a recent flurry of papers describing the importance of polarization
terms in getting good conformations which all the force fields you've
mentioned
have ignored.)  This heavy tuning of torsional terms has led to some
non-optimal
non-bonded terms.
    Another example of this is hydrogen bonds.  While Halgren has done
extensive work to get geometries of a large set of systems correct using
only charges and a buffered 7-14 term, as well as some energetics for these
systems, cases where there are strained H-Bonds fail because there
are just not enough terms to model the correct behavior at intermediate
distances, (where polarization dominates).
****************************************************

Responses from others:

1.  To me this force field seems more oriented towards providing good
geometries than energies. (we use MMFF geometries mostly to carry out
single-point calculations in view of estimating formation enthalpies).

2.  What is the experimental difference in energies?  Most force fields can
easily be in error by a kcal or two, and assuming that the experimental
difference is in that range all this result tells you is that the
developers probably didn't consider that specific compound when
developing the force field.  A useful article on what sorts of
conformational errors to expect is JACS volume 119, pages 5908-5920
(1997). 

3.  in principle this is the drawback of any molecular
mechanics method, you cannot make prediction with them, just reproduce the
type of molecule they have been parametrised with...

4. I performed the calculation using SYBYL.  Several force fields are
installed on the version that I am presently using.
1) MMFF94 with MMFF94 charges
equatorial conformer 1.408 kcal
axial conformer 1.061 kcal
This differs in detail from your result.  The author of the MMFF94
has published a test set.  That might be worth trying
in order to discover if Spartan has a faithful implementation
of MMFF94.
2) Tripos force field without charges
equatorial conformer 0.749 kcal
axial conformer 0.945 kcal
3) Tripos force field with Gasteiger charges
equatorial conformer 0.787 kcal
axial conformer 1.123 kcal
4)I haven't had time to explore an ab initio calculation.
In all case the energy difference is rather small.
Can you trust a modeling calculation in this case?
I am an experimentalist and naturally have a bias towards
data from microwave spectroscopy, NMR spectroscopy, and electron
diffraction.  In determining 3D structures from NMR data,
I combine modeling calculations with experimental constraints
that I obtain from nuclear Overhauser effect measurements.

> From: Gary Breton <[email-masked]>
> Date: Fri, 23 Feb 2001 12:37:53 -0500
> To: <[email-masked]>
> Subject: CCL:Question concerning Spartan molecular modeling software
> 
> Hello folks,
> 
> I hope at least some of you have some experience with PC Spartan Pro.  I
> recently purchased several copies of the software and began testing it with
> some routine molecular mechanics (MMFF94) calculations.  Amazingly, when I
> computed the energy of chlorocyclohexane with the Chlorine in the equatorial
> position ( 1.4 kcal/mol) it was of HIGHER energy than when the Cl was axial
> (1.1 kcal/mol).  This is contrary to experiment.  I ran the same calculation
> utilizing CambridgeSoft's Chem3D, with Hyperchem (MM+), and MOLGEN (MM2) and
> received the proper result (i.e., Cl prefers to be equatorial in the chair
> conformation) and the calculated energy differences were consistent with the
> experimental values.
> 
> Has anyone else observed this? is it a result of the force field? Am I doing
> something wrong in Spartan that I am NOT doing in the other packages?  If it
> is the force field, can I replace the parameters contained within Spartan?
> 
> Thanks for your help!
> 
> Gary W. Breton
> Department of Chemistry
> Berry College
> PO Box 495016
> Mount Berry, GA 30149
> 
> 
> 
> 
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---

From: Eric Bennett <[email-masked]>
Date: Tue, 27 Feb 2001 15:29:38 -0500

Gary Breton wrote:

> It would appear

That is not necessarily valid as a general principle.  A force field
that is well-parameterized for the specific system you are studying can
give better results than semi-empirical methods.  See for example the
Journal of Computational Chemistry, vol 12 number 2, pages 200-208
(1991) for some examples where MM2 predicts conformational energy
differences better than AM1 and PM3.  (And in most of the force field
reviews I have seen MMFF is usually as good as MM2, or better.)

-- 
Eric Bennett ( [email-masked] ; http://www.pobox.com/~ericb )