ECHET96 Article 051: Modeling Aqueous Environment

Ernest Chamot (
Tue, 25 Jun 96 09:28:40 EDT

I am one who particularly favors the use of theoretical descriptors in
developing a QSPR/QSAR: they are not only independent of the biases of the
analyst (in selecting "groups") and the training set (data is never
available for all possible derivatives), but are also useful for
interpretation of what chemical factors are controling the
system/interaction, etc. to give rise to the the observed property/activity.
So I like the approach of this paper.

I was wondering, however, whether the authors had considered modeling the
system with an implicit solvation model. They point out that their
calculations of theoretical descriptors are single molecule calculations.
The environment in which the molecules are biologically active, however, is
clearly not the gas phase, but presumably is more like an aqueous
environment (or perhaps within a membrane surrounded by an aqueous
environment). There are now at least two very good implicit solvation
models implemented with the AM1 semiempirical method. COSMO by Klamt in
MOPAC, and SM2 by Cramer and Truhlar in AMSOL. Both of these reproduce
specific solvation interactions with water very well, including local
geometry changes due to stabilization of a local dipole. COSMO and SM4 also
allow for the simulation of solvents other than water, although for this
work I would presume water is the most appropriate environment to consider.
At any rate, it would be interesting to see whether using the orbital
energies and/or the dipole moment (which I would expect to be strongly
stabilized by solvation) calculated using an implicit solvation model would
correlate better with the observed activity.

Some quick calculations (ie. just reoptimizing the geometries from the
structures as given in the .pdb molecule files in paper 51) suggest
significantly different theoretical descriptors with solvation. Modeling
ions 1 and 2 (piperydinium and pyrrolidinium) in an aqueous environment
(with the COSMO model) predicts greater dipole moments by about 2 Debye
(15.65 and 17.24 as aqueous vs. 13.73 and 15.06 as single ions), and the
HOMO and LUMO energies are shifted (consistently about 3.2 eV higher for an
aqueous environment).

It may be that everything gets shifted evenly to make no difference in the
final regression, but it should be more realistic to include solvation in
the calculation.


Ernest Chamot
Consultant in Computational Chemistry Applications
Chamot Laboratories, Inc.
530 E. Hillside Rd.
Naperville, Illinois 60540
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