“Procrustean bed”: Preliminary modelling of the very first steps of PrPC conversion to PrPSc through Molecular Dynamics

Introduction: Elucidation of the structure of PrP^Sc has opened the possibility to understand propagation of PrP^Sc (PrP^Sc-templated conversion of PrP^C to PrP^Sc) at the atomistic level. However, PrP^Sc offers a flat, “dull” templating surface with little templating capability. Therefore, the folded domain (FD) of PrP^C must unfold and stretch before it can be accommodated on the PrP^Sc surface.

Objectives: We modelled the very early steps of PrP^C unfolding once its flexible N-terminal 90-120 domain has easily attached to the PrP^Sc surface and adopted the PrP^Sc conformation.

Methods: We used Molecular Dynamics simulations at 310 K and 400 K in explicit water of a molecular system consisting of a PrP^Sc tetramer and a PrP^C(90-231) monomer with its 90-120 tail attached to it and having adoped the PrP^Sc conformation. Similar simulations of free PrP^C(90-231) were also carried out.

Results/Discussion: The FD of PrP^C(90-231) with its tail attached to PrP^Sc proved to be remarkably stable through 300 ns simulations. Even at 400 K it maintained its global fold and its 3 alpha-helices remained unscathed. Conformational fluctuations only affected significantly its internal coils and short β-strands. The N-terminal tail remained attached and the FD bounced into the PrP^Sc surface. In contrast, unfolding events were more conspicuous throughout simulations of free PrP^C(90-231). 

Conclusion: Our results highlight the “procrustean” predicament of PrP^Sc propagation, with a relatively stable FD facing a flat, relatively inert template. They also point to the relatively more flexible 121-143 N-terminal segment of the FD as a likely initiator of unfolding/refolding during conversion.