Structural instability of the prion protein upon M205S/R mutations revealed by molecular dynamics simulations

The point mutations M205S and M205R have been demonstrated to severely disturb the folding and maturation process of the cellular prion protein (PrPC). These disturbances have been interpreted as consequences of mutation-induced structural changes in PrP, which are suggested to involve helix 1 and its attachment to helix 3, because the mutated residue M205 of helix 3 is located at the interface of these two helices. Furthermore, current models of the prion protein scrapie (PrPSc), which is the pathogenic isoform of PrPC in prion diseases, imply that helix 1 disappears during refolding of PrPC into PrPSc. Based on molecular-dynamics simulations of wild-type and mutant PrPC in aqueous solution, we show here that the native PrPC structure becomes strongly distorted within a few nanoseconds, once the point mutations M205S and M205R have been applied. In the case of M205R, this distortion is characterized by a motion of helix 1 away from the hydrophobic core into the aqueous environment and a subsequent structural decay. Together with experimental evidence on model peptides, this decay suggests that the hydrophobic attachment of helix 1 to helix 3 at M205 is required for its correct folding into its stable native structure.