Mechanisms by Which Lipids Shape the Reaction Coordinate of GlpG Protease

Abstract

Rhomboid proteases are membrane-embedded enzymes whose catalytic activity depends on the composition of the lipid membrane that surrounds them. This makes rhomboids an excellent model system to dissect mechanisms by which lipids shape the reaction mechanisms of membrane proteins. Extensive all-atom molecular dynamics simulations of the Escherichia coli rhomboid, GlpG, indicate that the orientation of GlpG and lipid interactions at the substrate docking site, which are essential for substrate binding, depend on the lipid membrane composition. Different protein conformations can associate with different orientations in the membrane, suggesting that protein orientation is a dynamic parameter that changes during the reaction coordinate. The computations provide a comprehensive view of the molecular picture of GlpG/lipid interactions in different lipid membrane environments. This research was supported in part by funding from the Excellence Initiative of the German Federal and State Governments provided via the Freie Universität Berlin, and by an allocation of computing time from HLRN, the North-German Supercomputing Alliance (bec00076).