β-Hairpin-Mediated Formation of Structurally Distinct Multimers of Neurotoxic Prion Peptides

Abstract

Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies.

Effects of the Pathogenic Mutation A117V and the Protective Mutation H111S on the Folding and Aggregation of PrP106-126: Insights from Replica Exchange Molecular Dynamics Simulations

“…Our extensive REMD simulations show that the monomeric A117V mutated PrP106-126 exhibits the higher contents of β-hairpin in contrast with its wild type, consistent with the results of Monte Carlo simulations [ 22 ]. The CD spectroscopy experiments suggested that the A117V mutation increased β-sheet structure[ 30 ].…”

Nanostructures Formed by Custom-Made Peptides Based on Amyloid Peptide Sequences and Their Inhibition by 2-Hydroxynaphthoquinone

“…They looked similar to the disaggregation of amyloid fibrils by capreomycin (Siddiqi et al, 2018). The mesh of fibers in peptide P3 incubated with HNQ disappeared ( Figure 1B) as has been observed in similar studies on inhibitor action of 1,4-naphthoquinones (Gill, 2014), quinones (Gong et al, 2014), and other polyphenols (Ono et al, 2003), and copper (Mold et al, 2013) on amyloid formations. Amyloid β treated with white tea also showed amorphous aggregates whereas the overall density of aggregates was less in those samples treated with other types of tea (Li et al, 2019).…”

Self‐assembly of β‐turn motif‐connected tandem repeats of Aβ16‐22 and its aromatic analogs

“…These data suggest that hairpin‐like structures could be crucial in the assembly of other polyQ diseases as well. A molecular dynamics simulation study with the amyloidogenic fragments of murine Prion protein, PrP 109‐122 , PrP 106‐126 , and their Ala117Val mutants suggests that the assembly is mediated by β‐hairpin structures . Even though AβWW is not amyloidogenic, AβWW β‐turn analogs cause ~7‐10‐fold enhancement in ThT fluorescence intensity.…”

“…A molecular dynamics simulation study with the amyloidogenic fragments of murine Prion protein, PrP 109-122 , PrP 106-126 , and their Ala117Val mutants suggests that the assembly is mediated by β-hairpin structures. [47] Even though AβWW is not amyloidogenic, AβWW β-turn analogs cause~7-10- The structure of Aβ 14-23 fibrils has been investigated using solid-state NMR. [48] The fibrils are made up of antiparallel β-sheets with a registry that aligns residue 17+k with residue 22-k, where k is an integer.…”