As discussed earlier, the active site of the peroxygenases is relatively polar (with respect to CYP450BM3) due to carboxylate tail and an Arginine close to heme site. During the MD Simulations of both peroxygenases, the water occupancy was almost similar for all three water models (TIP3P, OPC, and SPC/E) which are gated by propionate side chain as shown in Figure . Though the aqueducts are rather similar to all the water modeled systems, we have found a significant difference in the behavior of the fatty acid substrate. During the MD with TIP3P and SPC/E modeled aqueous medium, the substrate strongly binds to the Arg245 residue through its carboxylate end and shows significant rigidity during the simulations in both peroxygenases. In contrast, during the MD simulations with the OPC modeled aqueous medium, the substrate slightly changes conformation over the course of time in both peroxygenases. Initially, the His363/H361 (CYP450OleT/CYP450BSβ) restricts the water accessibility, and the substrate interacts strongly through its carboxylate end with the guanidinium group of Arg245/Arg242. As the simulation progresses, the H363/H361 flips its orientation and allows an easy approach of water to the heme.