For the enzyme-substrate complex, we analyzed the last 35 ns of the stable trajectory using the same approach. However, in this case, clustering yielded geometries with toluene at the entrance of the active site, far from Cys493. Therefore, for QM:MM calculations, we selected the frame with the shortest distance (3.23Å) of the toluene group to the SH group of Cys493 which belongs to the first cluster which described the majority (54%) of the analyzed frames.