Restricted orientational disorder of the prion protein in complex with the innocuous antibody POM6.

Prion diseases are linked to the misfolding and aggregation of the cellular prion protein PrPC into the insoluble and toxic isoform PrPSc (scrapie), which then propagates itself by imposing its conformation onto PrPC. A proposed therapeutic approach to avoid the pathogenic transformation into PrPSc is to develop monoclonal antibodies that bind to PrPc and stabilize its conformation. POM6 is a monoclonal antibody that recognizes epitopes neighbouring those of POM1 in the globular domain of PrPC and is innocuous.

The movie shows the effect of the binding of POM6 (green for the heavy chain and blue for the light chain) on the interaction of PrPC (shades of purple) with the membrane. The movie emphasizes the closer distance of PrPC to the membrane surface and its restricted orientational disorder when compared to the state when the antibody is not attached.

Starting from the X-ray diffraction structure of POM6 complexed with the mouse prion protein (PDB ID: 6AQ7) simulations were performed using a hybrid Monte Carlo (MC) / molecular dynamics (MD) sampler. A fully atomistic representation of the complex POM1/PrPc was used and the complex was anchored to a coarse membrane via a GPI moiety (orange sphere). The membrane is modelled as a mimic of a flat layer of lipid headgroups. This mimic uses the simplest anionic function, carboxylates in acetate molecules, to represent different sources of negative membrane surface charge.