Antibody binding modulates the dynamics of the membrane-bound prion protein.

Misfolding of the cellular prion protein (PrPC) is associated with lethal neurodegeneration. PrPC consists of a flexible tail (residues 23-123) and a globular domain (residues 124-231) whose C-terminal end is anchored to the cell membrane. The neurotoxic antibody POM1 and the innocuous antibody POM6 recognize the globular domain. Experimental evidence indicates that POM1 binding to PrPC emulates the influence on PrPC of the misfolded prion protein (PrPSc) while the binding of POM6 has the opposite biological response. Little is known about the potential interactions between flexible tail, globular domain, and the membrane. Here, we used atomistic simulations to investigate how these interactions are modulated by the binding of the Fab fragments of POM1 and POM6 to PrPC and by interstitial sequence truncations to the flexible tail. The simulations show that the binding of the antibodies restricts the range of orientations of the globular domain with respect to the membrane and decreases the distance between tail and membrane. Five of the six sequence truncations influence only marginally this distance and the contact patterns between tail and globular domain. The only exception is a truncation coupled to a charge inversion mutation of four N-terminal residues, which increases the distance of the flexible tail from the membrane. The interactions of the flexible tail and globular domain are modulated differently by the two antibodies.