Quantum Mechanical Insights into Biological Processes at the Electronic Level - Computational Modeling of Biological Systems - page 144

Fig. 10 ( a ) ONIOM calculations were instrumental in identifying the “missing piece” in the
sequence of structures produced in the reaction catalyzed by tryptophan 2,3-dioxygenase. ( b )The
new proposed reaction mechanism that involves the “missing piece.” Adapted with permission
from [ 23 ]
the order of 30 10 6 configurations). The simulations were then coupled to the FEP
methodology for driving the reaction along the reaction coordinates, which were
chosen to be the N-O distance for the opening N-O bond of the substrate, and a
combined reaction coordinate for H-transfer, as shown in Fig. 11 b. The reaction
was slowly driven along these coordinates, and at each point on the reaction path
the system was equilibrated with MC. Thus, the free energy map for the reaction
was generated (Fig. 11 c). The mechanism of the catalyzed reaction is concerted,
with the proton transfer occurring slightly earlier and driving the subsequent N-O
bond opening. The overall G of the catalyzed reaction is slightly negative. The
activation barrier is 13.5 kcal/mol, which, when compared to that for the uncatalyzed
reaction in water (ca. 20 kcal/mol), indicates a catalytic effect, in agreement with
experimental results.