Molecular Dynamical Simulations of Point Mutation Occurring at the 198-th Site of Prion Protein

According to a kinetic model for understanding configurational conversion of the prion protein from PrP^C to PrP^Sc introduced by Morrissey and Shakhnovich [M. P. Morrissey and E. I. Shakhnovich, Proc. Natl. Acad. Sci. USA 96, 11293 (1999).], H1, an α-helix segment present in PrP^C, plays a vital role in the procedure. By employing molecular dynamics, we simulate the conversions of wild type, F198S, F198N, F198G, F198K, F198E, F198M, F198C, F198A, F198D, and F198T, in which F198S is known to induce the formation of PrP^Sc. Our simulations show that H1s in F198S, F198N, F198G, F198K, and F198E are less stable than H1s in the remaining six strains. Our results therefore suggest a possible scheme to test the kinetic model via experiment. Codons coding these amino acids may explain why transition from PrP^C to PrP^Sc induced by F198N, F198G, F198K, and F198E are not present in clinical observations.