Subject: Re: CCL:RMS Fits and Symmetries

From: Gregory Nikiforovich <[email-masked]>
Date: Wed, 10 May 1995 08:21:40 -0500 (CDT)

On Fri, 5 May 1995, James A Given wrote:

>   I have what I hope is a common problem. We are generating ligand
> conformations for use in drug design. The ligands we use can
> contain groups with various symmetries, e.g., benzene rings.  
> Does anyone know how to take such symmetries into account when 
> calculating RMS fit? 
> 
>   As a simple example of the problem that arises, imagine a 
> molecule with a plane of symmetry through its center. If the 
> molecule is flipped over and then superposed with the original, 
> the RMS calculation of the difference between the two should be zero. But a naive
> calculation of the RMS will not give zero, because the
> pairing of atoms induced by the superposition is not the
> identity pairing, i.e., the atom marked '1' in the original
> will not be coincident with the atom marked '1' in the copy. 

	The real trick is that in drug design you will have an "important"
	and "unimportant" atoms (or functional groups). So the only RMS what
	matters would be related to the "important" groups (i.e.: aromatics,
        H-bond donors/acceptors, ionized groups, etc.). In reality, you
	wouldn't encounter situations with the clear symmetry for the
	"important" groups. (Though, there are exceptions, like the symmetric
	HIV protease inhibitors.) On the other hand, if you are worried about
        non-coincidence of your atom "1" to a copy atom "1", what is the
        difference, if both atoms are the same, as in benzene case ?

##############################################################################

Gregory V. Nikiforovich                                   Phone (314) 935-4677
Research Professor                                        Fax   (314) 935-4979
Center for Molecular Design                            E-mail address:
Washington University                                  [email-masked]
Lopata Hall, Box 1099
St.Louis, MO 63130

##############################################################################

---

From: "Peter Shenkin" <[email-masked]>
Date: Wed, 10 May 1995 11:38:58 -0400

Subject: CCL:RMS Fits and Symmetries

> Does anyone know how to take such symmetries into account when

There are several ways of doing this.  The way MacroModel/BatchMin
does it is to define equivalence pairs of atoms;  for example,
if you have a phenyl group attached at the 1-position, two equivalence
pairs would be defined: 2-6 (the equivalent ortho positions) and 3-5
(meta). When calculating an RMS, our software would do it four times
for this ring, trying both possibilities for each pair, and would take
the lowest result.

Clearly, this could be done more smartly:  we could have a mechanism
to say that 2 and 3 (ortho and meta on one side of the ring) correspond
to 6 and 5 on the other, respectively;  then we would have to
calculate the best rigid-body superposition and residual RMS only
two times, instead of three.

A side-chain dressing program I wrote works in torsional space, and
does it another way.  The program is told that certain dihedral bonds,
such as chi2 of a PHE, TYR or ASP, and chi3 of a GLU, have 2-fold
symmetry.  (Another program might be smart enough to figure this out
for itself.)  Then any dihedral angle for such a torsion that falls
between 180 and 360 degrees gets 180 degrees subtracted from it
before it's compared to the analogous torsion in the other system.
(Of course, the mechanism is implemented in a general way; n-fold
local symmetry can be specified.)

Hope this helps,
	-P.

-- 
************************ The secret of life: *************************
*Peter S. Shenkin, Box 768 Havemeyer Hall, Chemistry, Columbia Univ.,*
* New York, NY  10027;     [email-masked];     (212) 854-5143  *
************* If you find a loose thread, don't pull it. *************