Subject: Questions re dielec. const. & conformers

From: "Hr Dr. S. Shapiro" <[email-masked]>
Date: Fri, 1 Sep 1995 13:11:33 +0100 (MET)

Dear Colleagues;

     I would like to be able to locate global minimum energy conformations
for molecules not only in the gas phase but also in solvents with different
dielectric constants, e.g., n-octanol or water.  I have examined several
molecular mechanics programmes, which have an adjustable dielectric constant
parameter as well as an option for using a distance-dependent dielectric.
However, the literature accompanying the programmes do not discuss at length
the matter of adjusting the dielectric.  For example, one programe has a de-
fault setting of 1.5 for the dielectric constant, and remarks that "It is
rare for increases in [the value of the dielectric constant] to reproduce the
properties of molecules in higher dielectric solvents, so this should be used
with great care. ... [The] distance-dependent dielectric constant ... option
 .... [has been] used successfully in the AMBER program when attempting to
model the effects of a polar solvent ...."

     My questions are as follows:

     (i) For molecular mechanics calculations, what is the _cut-off_ value
for the dielectric constant above which the results can no longer be regarded
as reliable?  5?  10? 25?  Does this upper limit for the value of the di-
electric constant depend on the force field implemented, or is it applicable
to molecular mechanics calculations employing _any_ force field?

    (ii) Solvents of prospective interest can have a wide range of dielectric
constants, from ca. 2 for n-alkanes and cycloalkanes to ca. 80 for water.
However, if I understand this correctly, a distance-dependent dielectric will
treat _all_ "higher" dielectric solvents equally, despite the fact that
values for "higher" dielectric constants can range over at least an order of
magnitude.  Can anyone offer any practical advice regarding the use of the
distance-dependent dielectric option in molecular mechanics calculations of
molecules in organic solvents?  Of course, references to any publications
directly addressing this matter are most welcome.

   (iii) In relation to the preceding two questions, I have a molecular
mechanics programme with a "dihedral driver" that will systematically rotate
a maximum of two bonds in a molecule per run, to generate an m x n matrix
in which each element corresponds to a particular conformation (and steric
energy) generated during that run.  Since the molecule in which I am inter-
ested has more than two conformationally-interesting bonds, I thought to ap-
ply the dihedral driver stepwise to pairs of bonds in order to locate a glo-
bal minimum energy conformation (lowest steric energy conformation of the en-
tire conformational space sampled) _in vacuo_, then feed that minimal energy
conformation to MOPAC with the COSMO subroutine engaged, assigning the value
of the dielectric constant of the solvent in which I am interested to "EPS".
(In other words, if I am interested in a molecule in the solvent n-octanol,
which has a dielectric constant of ca. 10, I would use "EPS=10" as one of my
keywords in MOPAC.)  However, I am not confident that the COSMO run will lead
to a global minimum energy conformation for the molecule in the solvent
rather than simply a local minimum closest to the input geometry.  Does any-
one have any suggestions, comments, or criticisms of the above strategy, ei-
ther with respect to the stepwise application of the dihedral driver or the
combination of molecular mechanical plus semi-empirical quantum mechanical
methods to try to find a global minimum energy conformation in a given sol-
vent?

     Thanks in advance to all responders.

Yours sincerely,

(Dr.) S. Shapiro
Inst. f. orale Mikrobiol. u. allg. Immunol.
Zent. f. Zahn-, Mund- u. Kieferheilkd. der Univ. ZH
Plattenstr. 11
Postfach
CH-8028 Zuerich 7
Switzerland

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