(544j) A Computational Study on Ionic Liquid Cation-Cytochrome P-450 Complexes Using QM/MM Calculations to Provide Structural Insights into Their Binding

Ionic liquids have been projected to be environmentally benign owing to their characteristics like inherent low vapor pressure and flammability. Their extremely low vapor pressures translate to the fact that they have negligible role in air emissions as compared to conventional industrial solvents. These liquids can also be flexibly designed in order to tune their physical properties. Out of the several already existing ionic liquid classes, imidazolium-based ionic liquids have been one of the most successfully utilized in diverse applications. Suitable variants of these types of ionic liquids have been applied in many process in the chemical industry. Though efficacious, investigations by various experimentalists have raised questions on their environmental degradability. Thus, including rational design into their synthesis becomes imperative. Despite a lot of experimental efforts in this direction, molecular level details have not been explored in detail computationally. The present work aims to provide physical insight into the phenomena of ionic liquid biodegradability to aid in the rational design of these solvents.

The Cytochrome P-450 enzymatic superfamily has been identified and widely studied for their role in oxidation of a wide variety of molecules in both aerobic and anaerobic environments. Former experimental work suggests oxygen insertion through hydroxylation at the terminal position of alkyl chains in the cation to aid in their ability to biodegrade. Thus, it was deemed necessary to capture the effects of the P-450 protein on imidazolium-based ([C_nmim]⁺) cations to develop a computational framework for their biodegradability. In the present work, the cations have been included in the model as substrates responsible for the reorganization of the binding pocket of cytochrome P-450. To capture the effects of substrate inclusion, the system was subjected to QM/MM calculations. The active site consisting of the heme molecule and the cation was treated at a quantum mechanical level (QM region) while the neighboring residues were treated at a classical level (MM region). Docking calculations were performed for generating suitable starting conformations for the above treatment. In the docking process, cations were inserted into the pocket varying the 1-n-alkyl chain on the cation progressively along the homologous series (n =2,4,6,8,10). Binding energy and other relevant analyses were performed on the resulting structures to provide mechanistic insights into the system. Also, the interaction strength between the heme and substrate molecules were also probed along with the stabilization of the QM region by the surrounding protein.