Investigation on the conformational conversion of human prion protein by molecular dynamics simulation

Conformational conversion of normal α-rich cellular prion protein PrP^C to its oligomeric β-rich isoform PrP^Sc can lead to fatal prion diseases. Despite numerous studies, the underlying mechanism for the β-enrichment during the conversion still remains elusive. In this molecular dynamics (MD) study, firstly, we examined the influence of pH on the PrP C-terminal domain and suggested that acidic pH can facilitate the denaturation of PrP which starts from H2 helix. After further conformational changes in the elevated temperature simulation and simulated annealing simulation, a new β-strand, named as S3, is formed at the denatured region of H2 and aligns antiparallel with native S2 β-strand, leading to a stable three-stranded β-sheet structure in the PrP C-terminal domain. With a combination of polarizable structure-specific backbone charge (PSBC) model and replica exchange molecular dynamics (REMD) simulation, we simulated the folding of three N-terminal fragment peptides. Three new β-strands are found. By incrementally modeling the newfound β-strand onto the previous three-stranded β-sheet structure, we obtained a novel β-rich conformer with six-stranded antiparallel β-sheet spanning both the C-terminal domain and the N-terminal amyloidogenic region of PrP, which might serve as the β-core of the amyloid fibrils and can provide important insights into the mechanism of the conformational conversion of PrP^C to PrP^Sc.​Doctor of Philosophy (SPMS