Backbone Engineering within a Latent β-Hairpin Structure to Design Inhibitors of Polyglutamine Amyloid Formation.

ABSTRACT: Candidates for the toxic molecular species in the expanded polyglutamine (polyQ) repeat diseases range from various types of aggregates to "misfolded" monomers. One way to vet these candidates is to develop mutants that restrict conformational landscapes. Previously, we inserted two self-complementary β-hairpin enhancing motifs into a short polyQ sequence to generate a mutant, here called "βHP," that exhibits greatly improved amyloid nucleation without measurably enhancing β-structure in the monomer ensemble. We extend these studies here by introducing single-backbone H-bond impairing modifications ^αN-methyl Gln or l-Pro at key positions within βHP. Modifications predicted to allow formation of a fully H-bonded β-hairpin at the fibril edge while interfering with H-bonding to the

SUBMITTER: Kar K 

PROVIDER: S-EPMC5286556 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature