Antibody binding increases the flexibility of the prion protein.

Prion diseases are associated with the conversion of the cellular prion protein (PrP) into a pathogenic conformer (PrPSc). A proposed therapeutic approach to avoid the pathogenic transformation is to develop antibodies that bind to PrP and stabilize its structure. POM1 and POM6 are two monoclonal antibodies that bind the globular domain of PrP and have different biological responses, i.e., trigger neurotoxicity mimicking prion infections (POM1) or prevent neurotoxicity (POM6). The crystal structures of PrP in complex with the two antibodies show similar epitopes which seems inconsistent with the opposite phenotypes. Here, we investigate the influence of the POM1 and POM6 antibodies on the flexibility of the mouse PrP by molecular dynamics simulations. The simulations reveal that the POM6/PrP interface is less stable than the POM1/PrP interface, ascribable to localized polar mismatches at the interface, despite the former complex having a larger epitope than the latter. In the presence of any of the two antibodies, the flexibility of the globular domain increases everywhere except for the β 1 - α 1 loop in the POM1/PrP complex which suggests the involvement of this loop in the pathological conversion. The secondary structure of PrP is preserved whereas the polar interactions involving residues Glu146, Arg156 and Arg208 are modified upon antibody binding. • The POM6/prion protein interface is less stable than the POM1/prion protein interface • Antibody binding increases the flexibility of the PrP globular domain, except in the β 1 -α 1 loop which is part of the epitope • The network of intramolecular contacts is perturbed differently upon antibody binding • The binding of the antibodies stabilizes the 3 10 -helix at the C-terminus of α 1 , with POM6 having a more pronounced effect. [ABSTRACT FROM AUTHOR]