Mutations and seeding of amylin fibril-like oligomers.

Seeding a protein solution with preformed fibrils can dramatically enhance the growth rate of amyloids. As the seeds do not need to be of the same protein, seeding may account for the observed correlations between amyloid diseases. In an effort to understand better the molecular mechanisms behind cross seeding we have studied in silico the effect of mutations on the seeding of amylin fibrils. Our investigations of the structural stability of decamers of wild type amylin peptides, of Y37L mutants, and of heteroassemblies of wild-type and mutant amylin molecules show that the experimentally observed efficient cross seeding can be explained based on similarity in fibril structure of components. We find that amyloids with similar side chains packing at the β-sheet interface are structurally compatible, acting as a good template for the congruent incorporation of homologues peptides. In the Y37L mutants, lack of tyrosine-specific interactions causes significant higher flexibility of the C terminal than observed in the wild-type fibril. This effects elongation of the mutant fibril leading to the longer lag times during aggregation that are observed in experiments. Our study gives guidelines for the design of ligands that could stabilize amylin fibrils.