Prions are unconventional pathogens that encode the pathogenic information in conformations of the constituent abnormal isoform of prion protein (PrPSc), independently of the nucleotide genome. Therefore, conformational diversity of PrPSc 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 PrPSc structures. Here we analyzed the influence of different hydrophobic residues on the structures of an in-register parallel β-sheet amyloid of α-synuclein (αSyn) using molecular dynamics (MD) simulation and applied the knowledge from the αSyn amyloid to modeling a local structure of human PrPSc encompassing residues 107-143. We found that mutations equivalent to polymorphisms that cause transmission barriers substantially affect the stabilities of the local structures; for example, the G127V mutation, which makes the host resistant to various human prion diseases, greatly destabilized the local structure of the model amyloid. Our study indicates that subtle differences among hydrophobic side chains can considerably affect the interaction network, including hydrogen bonds, and demonstrates specifically how and in what structures hydrophobic residues can exert unique effects on in-register parallel β-sheet amyloids.
© 2022 The Authors. Published by American Chemical Society.