Dataset Information

Understanding beta-hairpin formation.

ABSTRACT: The kinetics of formation of protein structural motifs (e.g., alpha-helices and beta-hairpins) can provide information about the early events in protein folding. A recent study has used fluorescence measurements to monitor the folding thermodynamics and kinetics of a 16-residue beta-hairpin. In the present paper, we obtain the free energy surface and conformations involved in the folding of an atomistic model for the beta-hairpin from multicanonical Monte Carlo simulations. The results suggest that folding proceeds by a collapse that is downhill in free energy, followed by rearrangement to form a structure with part of the hydrophobic cluster; the hairpin hydrogen bonds propagate outwards in both directions from the partial cluster. Such a folding mechanism differs from the published interpretation of the experimental results, which is based on a helix-coil-type phenomenological model.

SUBMITTER: Dinner AR

PROVIDER: S-EPMC17733 | biostudies-literature | 1999 Aug

REPOSITORIES: biostudies-literature

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Understanding beta-hairpin formation.

Dinner A R AR Lazaridis T T Karplus M M

Proceedings of the National Academy of Sciences of the United States of America 19990801 16

The kinetics of formation of protein structural motifs (e.g., alpha-helices and beta-hairpins) can provide information about the early events in protein folding. A recent study has used fluorescence measurements to monitor the folding thermodynamics and kinetics of a 16-residue beta-hairpin. In the present paper, we obtain the free energy surface and conformations involved in the folding of an atomistic model for the beta-hairpin from multicanonical Monte Carlo simulations. The results suggest t ...[more]

PMID: 10430896

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Project description: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.

Dataset Information

Understanding beta-hairpin formation.

Publications

Understanding beta-hairpin formation.

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