Subject: Re: charges schemes with CoMFA

From: [email-masked] (Tudor Oprea)
Date: Fri, 10 Feb 1995 09:47:06 -0700

I will not discuss the impact of choosing partial charges in conformational
analysis (CA), for two reasons: their magnitude (and "correctness") will
influence the choice of your local minima [to the extent that empirical 
charges may give a different energy map than quantum-mechanical ones],
and the choice of the dielectric D will definitely contribute to that
[smaller D will result in higher probability of intra-molecular H-bonds].
MNDO ESP calculations may be slow in MOPAC, but they correlate well with
631G* ESP charges - 0.94-0.96 R^2 for charge to charge correlation -
better than STO-3G ESP for the same molecules [these with G92].
PM3 has been previously reported to go wrong with Nitrogens - it was
previously posted on CCL - so browse in the 93-94 archive and look for
messages from Drs JJP Stewart, A Holder, E Zoebisch [and others...].

In CoMFA, the choice of charges does not matter as long as you are consistent
throughout the series: "If you can't be right, be consistent" (David Patterson).
In my experience, MNDO vs MNDO ESP charges have no significant impact on
the sets I studied. Of course, there might be some tricky ones out there 8=)
but for systems where no fancy electronic distribution occurs, MNDO or AM1
can do the works. Chris Waller has noted that PM3 gives better correlations
than Gasteiger-Huckel, but I would point out that both models were correlating
well in CoMFA. A paper I reviewed (I believe it is out in JMC) reported on the
side that comparing AM1 vs Gasteiger-Marsili, they found no difference.
In sum, as long as your CA results are ok, your CoMFA model is unlikely
to yield significant differences by using different partial charges.
As for the dielectric in CoMFA - I recently started using constant D instead
of distance dependent one - again, it is unlikely to have a tremendous
impact on the robustness/predictive/explanatory qualities of your model.

--Tudor

****************************************************************************
*  Tudor I. Oprea, MD PhD			Tel: (505) 667 2682	   *
*  Postdoctoral Research Associate		Fax: (505) 665 3493        *
*  Theoretical Biology and Biophysics (T-10)	Email:			   *
*  Los Alamos National Laboratory		[email-masked]	   *
*  Mail Stop K710, Los Alamos NM 87545					   *
****************************************************************************