Subject: Re: CCL:Re: CCL:HyperChem: Incorrect geometries in amines

From: Jochen Kuepper <[email-masked]>
Date: Thu, 4 Dec 1997 11:07:16 +0100

:> >  I am a user of HyperChem, version 4. Whenever I use molecular mechanics
:> > with the MM+ force field, to geometry optimise molecules such as
:> > Phenylamine (C6H5NH2), the geometry about the N atom is planar rather than
:> > pyramidal, i.e., an atom type of N2 is used for the nitrogen atom, rather
:> > than N3 as would be expected. I get the same result with molecules such as
:> > H2C=CHNH2 or H2C=NNH2. I also get incorrect geometries if I initially use
:> > the model builder to obtain an approximate geometry for such molecule or
:> > if I use any of the other three force fields available within HyperChem.
:> > If I initially set the atom type for the nitrogen atom to be N3, I still
:> > get an planar geometry about the nitrogen atom. 
:> > 
:> >  However, for molecules such as methylamine and cyclohexamine, i.e., where
:> > the atom bonded to the nitrogen atom is saturated, the correct geometry
:> > and atom type are obtained for the nitrogen atom. 
:> > 
:> >  Has anyone else experienced this problem?
:> 
:> Unless I'm missing the point here what you see is not a problem - simply
:> the correct answer. The nitrogen in these systems WILL be planar due to
:> the pi systems delocalising over all conjugated atoms. This forces the
:> nitrogen into planarity...something which won't happen with a saturated
:> system as there is no opportunity for pi orbital delocalisation. Might I
:> suggest reading something like 'A guidebook to mechanism in organic
:> chemistry' by Peter Sykes which has an excellent chapter on atomic
:> orbitals and hybridisation.

Actually Aniline (phenylamine) in _not_ planar !
There is a complete substitution structure determined/published by Larson !

But Andy's argumentation is ok at this level of theory (Hyperchem ?-),
MM, ... ?
So, that's why these calculation give 'wrong' results (in any way).

Jochen

PS: To be sure to have calculated something wrong, you need to measure it !!!

-----------------------------------------------------------------------
  Jochen Küpper

  Heinrich-Heine-Universität Düsseldorf     [email-masked]
  Institut für Physikalische Chemie I
  Universitätsstrasse 1, Geb 26.43.02.19       phone ++49-211-8113681
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-----------------------------------------------------------------------

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From: Pieter Stouten <[email-masked]>
Date: Thu, 04 Dec 1997 09:01:39 -0500

>But Andy's argumentation is ok at this level of theory (Hyperchem ?-),
There actually is at least one forcefield (MSI's CFF96) that is used in
Molecular Mechancis that does have properly puckered nitrogens. Are there
any other forcefields people know of, that do describe aniline etc.
properly?

Thanks,

Pieter Stouten <[email-masked]>
DuPont Merck - Computer Aided Drug Design Group
Web: http://www.halcyon.com/stouten/

---

From: Fabrice Leclerc <[email-masked]>
Date: Thu, 4 Dec 1997 10:53:33 -0500 (EST)

The Merck force field (MMFF94) does have properly puckered nitrogens
as well. It gives a geometry very close to what you get with CFF96
(0.03A).

---

From: "Peter Shenkin" <[email-masked]>
Date: Thu, 4 Dec 1997 11:09:20 -0500

On Dec 4,  9:01am, Pieter Stouten wrote:
> Subject: CCL:HyperChem: Incorrect geometries in amines
 ..
> any other forcefields people know of, that do describe aniline etc.

Hi, Pieter and CCL,

MMFF makes sp2 N's non-planar by default as well;  however, there
is an option to make them planar.  This option might be useful for
comparing computational results to crystal structures for large
molecules, where one would expect either thermal averaging or
the refinement procedure to make these atoms "appear" planar.

The so-called "MMFFs" (s for "static") option was added by Halgren
because of demand by Merck's crystallographic group, if I recall
properly.

	-P.

-- 
*********** In memoriam, Stephane Grappelli, 1908 - 1997, RIP *************
* Peter S. Shenkin; Chemistry, Columbia U.; 3000 Broadway, Mail Code 3153 *
** NY, NY  10027;  [email-masked];  (212)854-5143;  FAX: 678-9039 ***
*MacroModel WWW page: http://www.columbia.edu/cu/chemistry/mmod/mmod.html *

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From: Pieter Stouten <[email-masked]>
Date: Thu, 04 Dec 1997 11:51:11 -0500

Hello Peter and CCL,

>the refinement procedure to make these atoms "appear" planar.
If by "large" you mean proteins, then there is no problem as protons are
not observed (unless the structure is based on neutron diffraction data).
What would the comparison tell you if you knowingly use a "wrong" force
field to make the results look like crystal structures?

>because of demand by Merck's crystallographic group, if I recall
And again we may come full circle :-). E.g. peptide bonds can to a large
extent be restrained to planarity when solving crystal structures, then
forcefields are fitted ("compared") to these data, the forcefields are used
again in xray refinement and the world is good because all peptide links
are planar. It is concerning that there is even the option to make
forcefields fit the skewed crystallographic perspective <g> (don't flame
me! I was a happy crystallographer in a previous life).

Cheers,

Pieter

*** Note my new e-mail address: [email-masked] ***

Pieter Stouten                              ||  Nothing shocks me;
Computer Aided Drug Design Group            ||
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From: Richard Gillilan <[email-masked]>
Date: Thu, 04 Dec 1997 13:31:37 -0500

Peter Shenkin wrote:

> because of demand by Merck's crystallographic group, if I recall

Does anyone know if the MMFFs parameter set is published
anywhere?

Also, the original MMFF94 was not paramterized to reproduce liquid
properties as well as say OPLS. Does anyone know if this problem has
been addressed yet?

Richard Gillilan
[email-masked]

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From: "Peter Shenkin" <[email-masked]>
Date: Thu, 4 Dec 1997 13:17:22 -0500

Hello again, Pieter and CCL,

Yes, you make several good points.

On Dec 4, 11:51am, Pieter Stouten wrote:
> Subject: Re: CCL:HyperChem: Incorrect geometries in amines
 ...
> not observed (unless the structure is based on neutron diffraction data).

Yup.  It would be interesting to know whether the nonplanarity of
amide N's in proteins can be detected in neutron-diffraction studies.
I suspect that there is still sufficient reliance on force-field
assumptions during refinement that your accusation of circular
reasoning remains valid.

However, there is also the point that protein crystals are very 
floppy, and one might expect these non-planarities, which are
small, to be time-averaged out.

This discussion is similar to the question whether proteins can 
be adequately modeled in torsional space, given reasonable rigid 
values of the bond lengths and angles.  That question has been 
extensively examined, and perhaps this amide-puckering question 
deserves the same kind of examination.

I have personally done some conformational searches on peptides
using both versions of MMFF, and in some situations it did seem 
to make a difference.  What you'd really want to know is whether
two rather different overall conformations can have their relative
energetic stability seriously altered by requiring the sp2 N's to
be planar.

	-P.

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From: "Peter Shenkin" <[email-masked]>
Date: Thu, 4 Dec 1997 13:54:55 -0500

...
> Does anyone know if the MMFFs parameter set is published

J. Comp. Chem, 1996, v.17, five articles covering pages 490-641.
 
> properties as well as say OPLS. Does anyone know if this problem has

I believe not.

	-P.