Orientational disorder of the prion protein attached to a membrane surface.

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. POM1 is a monoclonal antibody that recognizes epitopes in the globular domain of PrPC and is neurotoxic.

The movie shows the high orientational flexibility of the prion protein with respect to the membrane surface as compared to the state when POM1 is attached to PrPC.

Starting from the solution NMR structure of the globular domain of the mouse prion protein (PDB ID: 1XYX) simulations were performed using a hybrid Monte Carlo (MC) / molecular dynamics (MD) sampler. A fully atomistic representation of PrPc was used and the prion protein 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.