Formation of β-sheets in glutamine and alanine tripeptides.

The misfolding and aggregation of proteins is associated with many different diseases including the trinucleotide repeat disorders and Prion diseases. We have studied three residue peptides comprising alanine and glutamine in order to understand the short range interactions affecting the formation of β-rich aggregates. Using infrared spectroscopy, we have found that trialanine and triglutamine form significant amounts of β-sheet, but that tripeptides containing alanine and glutamine are only able to form β-sheet if the glutamine side-chains extend outward on both faces of the sheet.

Mechanistic studies of peptide self-assembly: transient α-helices to stable β-sheets.

The pathologic self-assembly of proteins is associated with typically late-onset disorders such as Alzheimer's disease, Parkinson's disease, and type 2 diabetes. Important mechanistic details of the self-assembly are unknown, but there is increasing evidence supporting the role of transient α-helices in the early events. Islet amyloid polypeptide (IAPP) is a 37-residue polypeptide that self-assembles into aggregates that are toxic to the insulin-producing β cells.

Fiber diffraction as a screen for amyloid inhibitors.

Targeting the initial formation of amyloid assemblies is a preferred approach to therapeutic intervention in amyloidoses, which include such diseases as Alzheimer's, Parkinson's, Huntington's, etc., as the early-stage, oligomers that form before the development of beta-conformation-rich fibers are thought to be toxic. X-ray patterns from amyloid assemblies always show two common intensity maxima: one at 4.

The alpha-helix folds more rapidly at the C-terminus than at the N-terminus.

The helix-coil dynamics of different sections of an alpha-helical model peptide were observed separately by nanosecond temperature jump experiments with IR detection on a series of isotopically labeled peptides. The results show that the helix-coil dynamics of the alpha-helical C-terminus are faster than those of the N-terminus.

Experimental evidence for the reorganization of beta-strands within aggregates of the Abeta(16-22) peptide.

Amyloidogenic deposits that accumulate in brain tissue with the progression of Alzheimer's disease contain large amounts of the amyloid beta-peptide. A small fragment of this peptide, comprising residues 16-22 (Abeta(16-22)), forms beta-sheets in isolation, which then aggregate into amyloid fibrils. Here, using isotope edited infrared spectroscopy to probe the secondary structure of the peptide with residue level specificity, we are able to show conclusively that the beta-sheets formed are antiparallel and, following an anneal cycle or prolonged incubation, are in register with the central residue (Phe19) in alignment across all strands.

Intersheet rearrangement of polypeptides during nucleation of {beta}-sheet aggregates.

Many neurodegenerative diseases are characterized by the accumulation of amyloid fibers in the brain, which can occur when a protein misfolds into an extended beta-sheet conformation. The nucleation of these beta-sheet aggregates is of particular interest, not only because it is the rate-determining step toward fiber formation but also because early, soluble aggregate species may be the cytotoxic entities in many diseases. In the case of the prion peptide H1 (residues 109-122 of the prion protein) stable amyloid fibers form only after the beta-strands of the peptide have adopted their equilibrium antiparallel beta-sheet configuration with residue 117 in register across all strands.

Correlations among morphology, beta-sheet stability, and molecular structure in prion peptide aggregates.

The misfolding of proteins into beta-sheets and the subsequent aggregation of these sheets into fibrous networks underlies many diseases. In this paper, the role of peptide structure in determining the ordering of beta-sheet aggregates and the morphology of fibrils and protofibrils is dissected. Using a series of peptides based on residues 109-122 of the Syrian hamster prion protein (H1) with a range of substitutions at position 117, the link between side chain interactions and beta-sheet thermal stability has been investigated.