Chemistry Reference
In-Depth Information
Fig. 11 Prepared structure of the irreversibly inhibited cathepsin B enzyme. The preparation
started from the 1ITO X-ray structure [
129
]
However, not the irreversible but the reversible enzyme-inhibitor complex EI
(Scheme
1
) must be considered as reactant of the inhibition reaction. It is needed for
the investigation since, according to the Hammond postulate, the energetically
higher reactant tells us more about the transition state and, thus, about the reactivity,
than the product. However, X-ray data from this complex are not available since the
epoxide moiety is too reactive. To determine the reversible enzyme-inhibitor
complex, we computed the reaction path backwards from product (irreversible
complex) to the reactant (reversible complex). QM/MM reaction path calculations
were performed using DFT at the RIDFT [
130
]B[
108
]-LYP [
109
,
110
]/TZVP
[
111
] level for the QM part and the CHARMM force field for the MM part. In these
computations, the QM part comprises the inhibitor and the residues of the Cys29
and of the His199 moieties. The rest of the active site is in the MM-part.
