Subject: AM1 vs PM3 Charges in CoMFA?

From: [email-masked] (Tom Wiese)
Date: Wed, 13 Apr 94 14:04:14 -0400

Hello Netters,

I just read Dr. Holders comments about AM1 vs PM3.

What caught my interest the most was that part about PM3 charges being
"unreliable".

I would like to hear comments from those in the know as to which method of
generating charges, AM1 vs PM3, contributes to better/more useful CoMFA
models?

We have been using PM3 to generate structures and charges for various
steroidal estrogens that are used ultimately in CoMFA.  Compared to X-ray
data, we found that PM3 gives slightly better geometry than AM1 for typical
estrogens (Thomas E. Wiese and S. C. Brooks, "Molecular Modeling of Steroid
Estrogens: Novel Conformations and Their Role in Biological Activity" in
The Journal of Steroid Biochemistry and Molecular Biology, In Press).

However, we found AM1 to give very poor geometry of nitro and amino
substituted estrogen analogues when compared to PM3.  So, to be consistent,
we used PM3 for all compounds in the data set and have generated useful
CoMFA models.

I would also like to know if some body out there has a comment about
CoMFA's generated using geometry from PM3 and charges from AM1?

Thanks,

Tom

##################################################
Tom Wiese
Brooks Group
Department of Biochemistry
Wayne State University School of Medicine
540 E. Canfield
Detroit, MI
48201

Phone: (313) 577-5605
FAX: (313) 577-2765
email: [email-masked]
##################################################
##################################################

---

From: Tudor Oprea <[email-masked]>
Date: Wed, 13 Apr 1994 13:08:32 -0500 (CDT)

In my opinion, using one hamiltonian or the other is just a method to achieve
internally consistent models, and cross-validation is a mere test of the
internal consistency (or robustness).  As such, i do not think it is hamiltonian
dependent - after all, there are CoMFA models relying on AM1 optimized
geometries as well. As long as you are consistent for all the training set with
the charge-set and geometry, your correlation should hold true for both AM1 and
PM3, once the successful alignment rule has been discovered. 

With respect to charges, using AM1 vs PM3 should not yield a significant
difference (e.g., more than .2 in cross-validated r^2), and if it does, that
model becomes a problem (likely to be a spurious correlation).  Whatever
differences in charges are observed at, e.g., nitrogen atoms, unless those
charges are really important for biological activity, you are likely to get
similar regression analyses. After all, they would both be models, not
necesarrily reflecting the exact physico-chemical reality.

I do not exclude the possibility that, for some training sets, the PM3 charge /
geometry model to be significantly better (or worse) than its AM1 counterpart,
but I doubt that such findings would be general. 

--Tudor

                                                     ==========================
  Tudor-Ionel Oprea                                  = Tel. (1-314) 935 4672  =
  Research Associate                                 = Fax. (1-314) 935 4979  =
  Washington University Center for Molecular Design  = Email:                 =
  Lopata 510, Box 1099, One Brookings Drive          = [email-masked]  =
  St.Louis MO 63130                                  ==========================