Subject: Summary of replies on NAD and hydride transfer

From: "Dr. D.Eric Walters" <[email-masked]>
Date: Tue, 6 Dec 1994 12:46:08 -0600 (CST)

Following is a summary of replies to last week's question about hydride 
transfer.

>
> Is anyone aware of information on transition state geometry for hydride
> transfer to the nicotinamide ring of NAD?  I will appreciate any
> theoretical and/or experimental info you can provide.  Thanks!
>
> Eric  Walters
>
--------------------------
Eric,

I do not have a specific reference, but there was some work done in this
area by Houk and Wu (probably published in JOC).  I think I saw something
in 1993, but I know they were working on this as early as 1989.

Regards,

Susan Gustafson, Ph.D.
UniChem Support Specialist
Cray Research, Inc.

-----------------

I don't know if the specific system of a pyridinium structure
receiving a Hydride moiety from something like methanol
(i.e. Pyridinium + methanol => Dihydropyridine + formaldehyde)
has been theoretically studied. Orlando Tapia in Sweden had
use a smaller prototype, a cyclopropenium cation + hydride donor
and published something in JACS about 3-4 years ago. I don't have
the reference. I seem to remember larger systems being dealt with
in 1-2 papers in THEOCHEM in the last couple of years. Generally,
however, hydride transfer reactions have not been broadly dealt
with in ab initio theoretical chemistry. The hydride aspect
forces one to use a diffuse basis set (H(-) itself is not even
stable at the SCF level for any basis set, correlation is required
to approach the known electron affinity of H atom around 0.7 eV).
Therefore any credible ab intio calculation will probably be done
using a 6-31++G* basis or larger, this preventing any very large
systems from being treated.

I, myself, in a project with a Hungarian group, looked at
some hydride transfers related to a biologically related
reaction of reductive amination resulting from the reaction of
formaldehyde with ammonia, alkyl amines or free amino groups on
amino acids.  Reductive amination is a standard reaction discussed
in organic text books (e.g. H2C=O + NH3 => H2C(-NH2)-OH =>
H2C=NH; followed by protonated H2C=NH reacting with H2C(-NH2)-OH
giving CH3NH2). This is currently unpublished but the reaction
is easy, i.e. activation energies are not large (less that about
15 kcal/mol) for reactions which are nearly isoenergetic.

With regard to a calculation of full model of DPNH, in a solvent
system, this is technically out of range in ab initio calculations
but a program like AMSOL could handle it semiempirically. Cramer
and Trular (see Journal of Computer Aided Design, 6 (1992) 629-666)
treat proton transfers from pyridinium, Their AMSOL program,
new version, could generate the transition states as optimized
in the solvent cavity. In earlier versions of the program, the
optimizations are slow, but technically possible now. In fact,
I would advise any ab initio calculation to be preceded by a
semiempirical study first. The resulting semiempirical transition
states would likely be close to the ab inito ones, although
the formers energies are not too reliable. Doing ab initio
calculations using a continum solvent model is a formidable
task since the ab intio programs capable of doing so are not
being generally distributed yet. Although massively parallel
ab initio programs capable of handeling such a calculation are
now being developed, I'd say we are 1-3 years away from seeing
very many calculations coming out of these newly developing
technology. The AMSOL program is available thorugh QCPE or
commercially available as included in AMPAC 5 or SPARTAN. The latter
does both ab initio and semiempirical calculations but has
a solvent model only in the case of the latter.

regards

E. M. Evleth
Dynamique des Intereactions Moleculaires.
Universite Pierre et Marie Curie
4 Place Jussieu, Tour 22, Paris 75240
33-1-44-27-42-08 (work), 33 = France; 1 = Paris
33-1-45-48-67-20 (home),FAX 33-1-44-27-41-17 (lab)
--------------------------

        I am not sure whether you are interested in the following:
JACS, 113, 2353 (1991); JOC, 58, 2043 (1993).  These are article by
K. Houk and Y-D Wu.  I think they have a more recent article on this
area.

Ida
------------------------------
Eric,
I am doing calculations on the reaction profile in malate dehydrogenase that
has both proton and hydride tranfer reactions.  The hydride reaction is
from malate to the nicotinamide of NAD.  We use a combined AM1
semiempirical/CHARMM MM Hamiltonian that I have developed.  We calculated
the entire reaction profile for this system, which includes transition
state geometries.

Maybe some of our results would be useful for you??

Paul Bash
Argonne National Laboratory
Bldg 202/A349
9700 S. Cass Avenue
Argonne, IL. 60439
[email-masked]
Phone: 708-252-8631 (work)
Phone: 312-642-3029 (home) I often work at home.
Fax: 708-252-5517
----------------------------------------
Thanks to all who replied!

Eric

* D. Eric Walters, Ph.D., Associate Professor, Biological Chemistry
* Finch University of Health Sciences/The Chicago Medical School
* 3333 Green Bay Road, North Chicago, IL  60064
* ph 708-578-3000, x-498;fax 708-578-3240; email: [email-masked]
* "A man would do nothing if he waited until he could do it so well that
*  no one would find fault with what he had done." --Cardinal Newman