Subject: CCL: CoMFA: charge schemes

From: "Konrad, IRBM Chemistry, +39-6-91093606" <[email-masked]>
Date: Sat, 11 Feb 1995 16:57:22 +0100 (WET)

On 10-FEB-1995, Tudor Oprea wrote in response to Nick Tomkinson's post:

> 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].

   The latest version of MOPAC93 includes a new option, PMEP[1,2] which is at
least two orders of magnitude faster and more accurate (at reproducing 6-31G*
ESPFIT charges) than the old MOPAC ESP charges. 

[1] Ford, G. P.; Wang, B. A new approach to the rapid semiempirical calculation
    of molecular electrostatic potential based on the AM1 wave function:
    Comparison with ab initio HF/6-31G* results.  J. Comput. Chem.   1993, 14,
    1101-1111.
[2] Wang, B.; Ford, G. P. Atomic charges derived from a fast and accurate
    method for electrostatic potentials based on modified AM1 calculations.  J.
    Comput. Chem.   1994, 15, 200-207.

> 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. ... [rest of message deleted]

   The source of charges may not matter for systems like steroids or peptides,
where most commonly used methods (including Gasteiger-Marsili) give reasonable
charges.  But in my experience, the source of charges does make a _big_
difference for systems such as aromatic heterocycles.  We did a comparison of
ESPFIT 6-31G* [3] vs. MNDO Mulliken charges [3] vs. Gasteiger-Marsili
[unpublished].  The cross validated R2's were 0.71 vs. 0.65 vs. ~0.40
respectively.

[3] Allen, M. S.; La Loggia, A. J.; Dorn, L. J.; Martin, M. J.; Costantino,
    G.; Hagen, T. J.; Koehler, K. F.; Skolnick, P.; Cook, J. M. Predictive
    binding of b-carboline inverse agonists and antagonists via the
    CoMFA/GOLPE approach. J. Med. Chem.   1992, 35, 4001-4010.

    The use of consistent charges will of course cancel systematic errors in
the charges.  However, if the errors are random and if the electrostatics
(relative to sterics, hydrophobicity, etc.) are an important part of the
correlation, then bad charges will produce bad correlations. 

    Ciao,

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