Chemistry Reference
In-Depth Information
An excellent approximation for the protein environment is the p/s situation. It
uses the geometry of the enzyme-inhibitor complex but approximates the environ-
ment through a continuum approach (COSMO,
78) which simulates a polar
solvent. For the C-O2 bond, this approach deviates even less from the p/p results
than the data computed for crystals of the pure compound (c/c). In all other cases
both approaches are very similar. Their deviations from the protein data are well
below 10%.
The computed dipoles (Table
15
) reveal similar trends as the bonding parameters.
Compared to the gas phase (g/g), we compute dipole enhancements of 46% for the
protein environment and 37% for the surrounding inside of crystals of the pure
compound. The latter increase resembles values compiled in a recent overview from
Spackmann et al. [
20
] and matches those found by Gatti et al. for urea [
122
] crystals,
which, analogously to AMCHA, contains C
¼
O and NH
2
groups interacting through
H-bonds. The environment inside crystals of the pure compound mimics the influ-
ence of the protein surrounding very accurately despite the differences in the geo-
metries of AMCHA. As already found for the ED and its Laplacian, the p/s situation
represents an excellent approximation to the p/p computation. A comparison between
s/s and p/s shows that the strong dipole enhancement in the protein results partly from
the geometry of AMCHA in the protein.
Table
16
offers a more detailed picture about the influence of the environments
on the charge distribution of AMCHA. The table collects atomic charges computed
with the Roby-Davidson partitioning [
123
,
124
]. If the gas phase is compared with
the protein environment, a slight increase in the absolute values of the partial
charges of the carboxylate and the ammonium group can be found. In this case
the partial charge of the carboxylate changes from
e
¼
1.02, i.e., for about
0.5 units. An increase of about 0.1 is found for the ammonium group. These
changes are consistent with the results on the ESPs (Figs.
9
and
10
). The increase
due to the protein environment is strongest, but the surrounding in crystals of the
pure compound and the polar solvent environment yield comparable enhancements,
i.e., both represent very good approximations of the protein surrounding.
As also found for enzyme-substrate reactions, the inhibition mechanisms of
irreversible inhibitors include covalent bond formation and rupture. Thus, it seems
likely that enzyme environments influence EDs of irreversible inhibitors in a
similar way as they do for substrates. However, the enzyme environments have
0.56 to
Table 15 Influence of the
environment on the dipole
moment of AMCHA
Geom/prop Dipole moment/a.u.
g/g 10.6
s/s 14.1
p/p 15.5
p/g 11.1
p/s 14.5
c/c 14.5
c/g 11.1
c/s 14.0
All values are given in (a.u.). An explanation of the abbrevia-
tions can be taken from Table
8
