Subject: AM1 conf.analysis

From: [email-masked] (Jonathan Baell)
Date: Tue, 19 Apr 94 08:28

Dear Steven,

A year or so ago I wanted to do a similar thing and my impressions are as 
follows.

I would suggest to use the later versions of AM1 which include parameters 
for sulfur and phosphorous.  AM1 in general would seem to have fewer 
faults than MNDO - and is more "tried and tested" than PM3 - in 
predicting correct geometries in conjugated systems and in estimating 
hydrogen bonding interactions and tautomerism (see Fabian, J. Comp. Chem. 
12, 17-35 (1991)), although it's worth knowing some of its limitations 
with respect to underestimation of rotational barriers (see Fabian, J. 
Comp. Chem. 9, 369-377 (1988)).

For ease and accuracy in conformational studies of non-conjugated (and 
not too unusual) fragments I would use MM2 or MM3 (see Gundertofte et al, 
J. Comp. Chem. 12, 200-208 (1991).

Remember to consider the effects of solvent and dielectric constant to 
reflect the environment which your biological results represent.  This is 
relevant even if the bioassay has significant "in vivo" character as you 
can factor out the effect that molecular hydrophobicity has on transport 
to the active site (as no doubt you are aware).

In vacuuo semiempirical calculations can lead to significant problems 
when extending the results to a system in, for example, water, and it 
used not to be a trivial matter to incorporate these effects into such 
calculations (see Karelson et al, J. Org. Chem. 54, 6030-6034 (1989)) 
without explicit inclusion of water molecules.  However, AMSOL, with 
which I am unfamiliar, may be the "solution" for these cases.

While AM1 outcompetes MNDO with respect to most geometrical calculations, 
it is MNDO ESP charges that most closely match 6-31G*-derived point 
charges (see Besler et al, J. Comp. Chem. 11, 431-439 (1990) and Merz 
Jr., J. Comp. Chem. 13, 749-767 (1992)).  Thus if you're not happy with 
the assumption that molecular mechanics calculations at a constant 
dielectric of 1 and without electrostatics can be used to reasonably 
reflect the behaviour of the corresponding charged system in water (or 
the active site), you might want to look at varying the dielectric 
constant using the MNDO-ESP (scaled) charges.  Whether you set the 
dielectric to 78 (water) or 4 (a value I've seen recommended for a 
ligand-protein interface), or a value somewhere in between, or whether 
you vary the dielectric with distance, I do not know which is best.....
         .........
                   .........and would be interested in any information 
>from anyone on what is regarded as the most recommended approach with
respect to the consideration of dielectric in ligand-protein 
interactions, where the protein may or mayn't be membrane-bound: is it a 
"highly individual" treatment, depending greatly on the microenvironment 
(active site) more than the macroenvironment (membrane or water)?  I 
would have thought so.

Indeed, while on this point, I would have thought that the dielectric of 
the active site of proteins in membranes would tend to be relatively 
greater than that which occurs in proteins in an aqueous environment, 
because in this way nature wins out: in a non-polar macroenvironment a 
polar "microinteraction" (sorry about all this jargon) would be 
energetically favourable but in an aqueous macroenvironment a non-polar, 
hydrophobic active site would be required to produce a significant and 
far-reaching favourable interaction (for a hydrophobic ligand).  Does 
anyone know of a good discussion paper on active site dielectrics vs 
protein type?

Jonathan Baell