Molecular dynamics simulations of substrate channeling through an α–β barrel protein

Abstract Steered molecular dynamics simulations are used to probe the energetics of substrate channeling in an enzyme regulating histidine biosynthesis, imidazole glycerol phosphate synthase (IGPS). IGPS is a multidomain globular protein complex: the glutaminase domain hydrolyzes glutamine to form glutamate and ammonia, and is docked to the cyclase domain, a (β/α)8 barrel protein that completes the ring formation of imidazole glycerol phosphate. Recently, it has been suggested that this protein exploits its barrel structure to channel ammonia from one remote active-site to the other. The current work includes both domains, their substrates, ammonia, and explicit solvent. Compared to the apo-complex, the inclusion of substrates does indeed affect the barrier to ammonia entry into the channel as well its transport through the barrel. Based on bioinformatic data, we suggest an “open-gate” mechanism that has a low barrier to ammonia entry. We also perform the first systematic investigation of interface water molecules near the channel gate and argue that the optimum number of water molecules inside the channel is one.