Subject: conformational isomers

From: Mick Kappler <[email-masked]>
Date: Wed, 22 Feb 1995 12:20:36 PST

On Tue, 21 Feb 95 4:08:12 EST, Dongchul Lim wrote:

> Is there a simple way of testing if two given conformational isomers
> are equivalent?

Yes. The Stereochemical Extended Morgan Algorithm (SEMA) developed by Wipke
and Dyott provides a stereochemical canonical name.  Comparison of the
structure SEMA names is straight forward.

						Mick Kappler
						Molecular Engineering Laboratory						W. Todd Wipke Group
						Univ. of California, Santa Cruz

---

From: [email-masked] (Marvin Waldman)
Date: Wed, 22 Feb 1995 14:47:42 -0800

> Is there a simple way of testing if two given conformational isomers

This is, in fact, quite a difficult and subtle question.  The SEMA
algorithm which Mick Sappler proposed can be used to detect if
two CONFIGURATIONAL isomers are equivalent (ie. they have the
same or different stereochemistry).  However, it will not detect
if the same configurational isomers are equivalent or not in
a CONFORMATIONAL sense.  SEMA cannot detect the difference between
the gauche and trans forms of n-butane.  These are CONFORMATIONAL
isomers.

The issue of the equivalence of two conformations is further complicated
by the problem of topological symmetry.  This makes an RMS comparison
of atoms problematic for detecting equivalent conformations.  For
example, if I do an RMS comparison of corresponding atoms between
two conformers in which the hydrogens of a methyl group are rotated
by 120 degrees, I will detect an RMS difference because I am now
comparing the wrong set of atoms.  One needs to compare all combinations
of topologically equivalent atoms in the molecule to see if they
have a (virtually) zero RMS.  If one proposes to do an RMS comparison
of heavy atoms only, then you only need to replace the methyl group
with a t-butyl group, and the problem remains.  If one proposes to
compare only energies (and not RMS), then, of course, the symmetry
will be correctly handled for the energy, and you only need to
worry about the somewhat unlikely case of two different conformers
having (almost?) the same energy.  Since these conformers are likely
to come from some energy optimization procedure, roundoff error
and tolerances used for the minimization implies that one needs to
use some kind of tolerance in comparing energies, which always leads
to the (remote?) possibility that nearly equal energies may not
correspond to the same conformer.  The larger the molecule and the
more conformational flexibility (and therefore conformers) it has,
the more likely that this somewhat theoretical problem may manifest
itself in a real example.  The ideal/correct solution would be to
compare both the energy as well as all combinations of RMS comparisons
of topologically equivalent atoms until the RMS difference found
for a given comparison pair fell below some threshold.  I am not
aware of a software package that has actually implemented such
an algorithm, and would be very interested to hear about one that
does.

So, the bottom line answer to the question, is: No, I don't think
there is a SIMPLE way to do this.

Marvin Waldman, Ph.D.
Manager, Rational Drug Design
Biosym Technologies, Inc.
e-mail: [email-masked]