In silico evidence of unique behaviors of methionine in an in-register parallel beta-sheet amyloid, suggestive of possible contribution to strain diversity of amyloids.

Abstract

Mechanism of strain diversity of prions is a long-standing conundrum, because prions consist solely of abnormal isoform of prion protein (PrPSc) devoid of genetic material. Pathogenic properties of prions are determined by conformations of the constituent PrPSc according to the protein-only hypothesis, and alterations to even a single residue can drastically change the properties when the residue is located at a critical position for the structure of PrPSc. Interestingly, methionine (Met) is often recognized as the polymorphic or species-specific residues responsible for species/strain barriers of prions, implying its unique influences on the structures of PrPSc. However, how it is unique is difficult to demonstrate due to lack of the detailed structures of PrPSc. Here we analyzed influences of Met substitutions on structures of an in-register parallel {beta}-sheet amyloid of -synuclein (Syn) by molecular dynamics (MD) simulation, to extrapolate the results to PrPSc. The MD simulation revealed that Met uniquely stabilized a U-shaped {beta}-arch of the Greek-key Syn amyloid, whereas other hydrophobic amino acids tended to destabilize it. The stabilizing effect of Met was attributable to the long side chain without C{beta} branching. Our findings exemplify specifically how and in what structure of an in-register parallel {beta}-sheet amyloid Met can uniquely behave, and are suggestive of its influences on structures of PrPSc and strain diversity of prions. We also discuss about relations between -helix propensity and local structures of in-register parallel amyloids.