Conformation-dependent influences of hydrophobic amino acids in two in-register parallel β-sheet amyloids, an α-synuclein amyloid and a local structural model of PrPSc

Prions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrP Sc ), independently of the nucleotide genome. Therefore, conformational diversity of PrP Sc underlies the existence of many prion strains and species barriers of prions, although the conformational information is extremely limited. Interestingly, differences between polymorphic or species-specific residues responsible for the species/strain barriers are often caused by conservative replacements between hydrophobic amino acids. This implies that subtle differences among hydrophobic amino acids are significant for PrP Sc structures. Here, we analyzed the influence of different hydrophobic residues on the structures of an in-register parallel β -sheet amyloid of α -synuclein ( α Syn) using molecular dynamics (MD) simulation, and applied the knowledge from the α Syn amyloid to modeling a local structure of human PrP Sc encompassing residues 107–143. We found that mutations equivalent to polymorphisms that cause transmission barriers substantially affect the stabilities; for example, the G127V mutation, which makes the host resistant to various human prion diseases, greatly destabilized the model amyloid. Our study demonstrates specifically how and in what structures hydrophobic residues can exert unique effects on in-register parallel β -sheet amyloids and provides insights into the molecular mechanism of the strain diversity of prions and other pathogenic amyloids. For Table of Contents Only