Theoretical studies of sequence effects on the conformational properties of a fragment of the prion protein: implications for scrapie formation

AbstractBackground: Prion diseases are neurodegenerative disorders that appear to be due to a conformational change, involving the conversion of α-helices in the normal, cellular isoform of the prion protein (PrPC) to β-structure in the infectious scrapie form (PrPSc). One form of Gerstmann-Sträussler-Scheinker syndrome (GSS), an inherited prion disease, is caused by mutation of Alal17 of PrPC to Val. We therefore set out to evaluate the effects of this mutation on the stability of the PrPC form.Results: We have performed molecular dynamics simulations of a portion of the PrPc sequence (residues 109–122, termed H1) that is proposed to figure prominently in the conversion of PrPC to PrPSc In particular, beginning with H1 in the α-helical state, the conformational consequences of sequence changes at position 117 were investigated for six hydrophobic mutations. Of these, only the Val mutation was helix-destabilizing. Portions of this mutant peptide adopted and retained an extended conformation during a 2 ns simulation of the peptide in water.Conclusions: The conformational transitions and structures observed in the simulation of the mutant peptide with Val at position 117 provide insight into the possible early steps in the conversion of PrPC to PrPSc