Molecular dynamics simulation of local structural models of PrPSc reveals how codon 129 polymorphism affects propagation of PrPSc.

Abstract

Prions are unconventional pathogen without nucleotide genome and their pathogenic properties are defined by the primary structure and the conformation of the constituent abnormal isoform (PrPSc) of prion protein (PrP). A polymorphic codon 129 of human PrP that is valine (V129) or methionine (M129) is particularly influential on properties of PrPSc, affecting transmission efficiencies and clinicopathological features. However, how the single residue is so influential has not been elucidated because the detailed structures of PrPSc have not been determined yet due to its incompatibility with high-resolution structural analysis. Previously we created an in-register parallel {beta}-sheet local structural model of human PrPSc encompassing residues 107 to 143 that seemed more compatible with V129 than M129, based on knowledge from -synuclein amyloids and an NMR-based model of the amyloid of Y145Stop mutant of PrP in the literature. Here, we created an M129-compatible local structural model of PrPSc. Severe destabilization of the model by G127V mutation was consistent with the protective effects of V127 polymorphism of human PrP against prions. It was highly sensitive to the length of the hydrophobic side chain of codon 129 and replacement of M129 with leucine or valine destabilized the structures. Interestingly, the U-shaped {beta}-arch which comprises M129 flexibly changed hydrophobic interaction networks inside the {beta}-arch depending on the interactions with the surrounding structures, whereas the previous model with V129 maintained the similar network patterns irrespective of the surroundings. The differences between the two models may explain influences of the codon 129 polymorphism on transmissions and properties of human prions.