Antibody binding regulates the dynamics of the membrane-bound prion protein

Prion diseases are associated with the conversion of the cellular prion protein (PrP^C) into a pathogenic conformer (PrP^Sc). A proposed therapeutic approach to avoid the pathogenic transformation is to develop monoclonal antibodies that bind to PrP^C and stabilize its structure. POM1 and POM6 are two monoclonal antibodies that bind the globular domain of PrP^C and have different biological responses, i.e. trigger neurotoxicity mimicking prion infections (POM1) or prevent neurotoxicity (POM6). The crystal structures of PrP^C 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 and the interaction with the membrane of the mouse PrP^C by molecular dynamics simulations. The results show that in the presence of any of the two antibodies, the flexibility of the globular domain increases everywhere except for the ß₁-α₁ loop in the POM1/PrP^C complex, which is part of its epitope [1]. Additionally, the binding of the antibodies restricts the range of orientations of the globular domain with respect to the membrane, decreases the distance between both modules of PrP^C and the membrane, and restricts the orientational disorder of the globular domain. Furthermore, the interactions of the flexible tail and globular domain are modulated differently by the two antibodies [2].

[1] ILIE & Caflisch, BBA-Proteins Proteom. 1870, 140827 (2022)

[2] ILIE et al. Biophys. J. 121, 2813 (2022)