Effect of Environmental Factors on the Catalytic Activity of Intramembrane Serine Protease

The cleavage of protein inside cell membranes regulates pathological pathways and is a subject of major interest. Thus, the nature of the coupling between the physical environment and the function of such proteins has recently attracted significant experimental and theoretical efforts. However, it is difficult to determine the nature of this coupling uniquely by experimental and theoretical studies unless one can separate the chemical and the environmental factors. This work describes calculations of the activation barriers of the intramembrane rhomboid protease in neutral and charged lipid bilayers and in detergent micelle, trying to explore the environmental effect. The calculations of the chemical barrier are done using the empirical valence bond (EVB) method. Additionally, the renormalization method captures the energetics and dynamical effects of the conformational change. The simulations indicate that the physical environment around the rhomboid protease is not a major factor in changing the chemical catalysis and that the conformational and substrate dynamics do not exhibit long-time coupling. General issues about the action of membrane-embedded enzymes are also considered.