Transfer of arginine into lipid bilayers is nonadditive

Computer simulations suggest that the translocation of arginine through the hydrocarbon core of a lipid membrane proceeds by the formation of a water-filled defect that keeps the arginine molecule hydrated even at the center of the bilayer. We show here that adding additional arginine molecules into one of these water defects causes only a small change in free energy. The barrier for transferring multiple arginines through the membrane is approximately the same as for a single arginine and may even be lower depending on the exact geometry of the system. We discuss these results in the context of arginine-rich peptides such as antimicrobial and cell-penetrating peptides.