Chemistry Reference
In-Depth Information
representations of the Laplacian of E64c in the epoxide plane and gives the values
of
2
(
r
) at the (3,+1) critical points. For comparison, we also included the values
obtained if geometry and ED are determined in gas phase (g/g) or polar solvent (s/s),
respectively.
While Fig.
15
shows influences of the environment on the values of
r
r
2
r
r
(
r
)atthe
2
(3,+1) critical points, the general shape of
(
r
) does not change significantly in
comparison to data obtained for the protein geometry. Additionally, the sequence of
the electrophilicity of the carbon centers is not changed, i.e., C
b
always represents
the more electrophilic center. The
r
r
2
r
(
r
) values at the (3,+1) critical points increase
significantly if the gas phase environment (p/g) is replaced by a polar solvent (p/s)
or if the charge of the thiolate is changed from
r
1(p/pS
1
).
The latter effect owes to the repulsion of the negatively charged thiolate and the
electron cloud of the epoxide ring. Since the thiolate-C
a
distance is smaller, the
r
0.07 (p/p S
0
)to
2
(
r
) value at C
a
increases stronger than the one at C
b
. As found for AMCHA,
the polar solvent mimics the protein environment considerably better than the gas
phase approach.
The distortion of the epoxide ring induced by the protein environment is
clearly reflected in
r
2
C2-O1 bond) is considerably
weakened. The C
b
-O1 bond, on the other hand, is not affected. Combining the
present data with previous computations [
131
,
132
] about the kinetics, a clear
picture emerges as of how the interaction in the enzyme-inhibitor complex
influences the course of the subsequent reaction. Due to the strong bonding
interactions between the carboxylate group and the oxyanion hole and the
His199 residue, the epoxide ring is pulled so close to the thiolate that the epoxide
ring is strongly distorted toward the product structure. Due to the position of the
thiolate and the strongly weakened C
a
-O1 bond, only the
r
r
(
r
). The C
a
-O1 bond (
-attack takes place
despite the higher electrophilicity found for C
b
. This effect is strengthened by the
interactions between the enzyme and the peptidomimetic side chain. They clamp
E64c into the active site so that the
a
-attack is additionally disfavored. In total a
reaction barrier of only 1-2 kcal/mol was computed for the
b
a
-attack, while for the
b
-attack a barrier or 15 kcal/mol was predicted. Within the picture of a potential
energy surface, the regiospecificity is caused by the fact that the reactants are
pushed along the reaction coordinate toward the transition state. Looking at the
ED of the reactants, the significantly elongated C
a
-O1 bond is one of the main
reasons for the regiospecificity. Such special influences can, of course, not be
mimicked in pure gas phase (g/g) or solvent computations (s/s). Most probably it
is also not possible to deduce them from measurements performed for crystals of
the pure compound.
X-ray measurements of the crystal structure of E64c are not available. Hence, to
get a rough insight into the influence of the crystal environment on the electronic
structure of the epoxide moiety, we used X-ray data of E64d (Fig.
5
). In E64d the
carboxylate group of E64c is replaced by an ester moiety. The geometrical arrange-
ments of the units in crystals of pure E64d are depicted in Fig.
16
. Figure
17
summarizes the corresponding contour plot representations of
2
r
r
(
r
) and the
