Folding of an Ala-Ala-Ala Tripeptide into a β-Turn via Hydrophobic Encapsulation

Tashiro, Shohei; Kobayashi, Masahide; Fujita, Makoto

doi:10.1021/ja061722e

Cited by 78 publications

(46 citation statements)

References 10 publications

(12 reference statements)

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“…In this work, β-hairpin structures varied in relation to the number of turns – single, double and triple hairpin forms of peptides were found – as well as the location of the turns, but the majority of turns were of the β type and incorporated one of the glycine residues of the peptides. Glycine residues are known to be favored in β-turns as a result of the flexibility of the backbone torsional angles [63] whilst alanine residues, that comprise the central portion of the PrP peptides, are predominately helix-favoring but are also capable of turn formation [64]. Substitution of alanine 117 for valine, a mutation that is associated with inherited prion disease in humans [55] and which leads to enhanced toxicity of peptide aggregates in vitro [65], energetically destabilized helical folds and increased the proportion of peptides in β-hairpin conformation.…”

Section: Discussionmentioning

confidence: 99%

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

Gill

2014

PLoS ONE

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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.

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Section: Discussionmentioning

confidence: 99%

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

Gill

2014

PLoS ONE

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“…The title compound, 5,10,15,20-tetra(3-pyridyl)porphyrin (3TPyP) (1) (Scheme 1a), has also been used similarly but less frequently. Polynuclear metallosupramolecular complexes [12,13], two coordination polymers [14,15] and trigonal prismatic shaped coordination cages [16][17][18] bearing either free-base 1 or its Zn 2+ core metalated derivative have been reported. Most recently, Lipstman and Goldberg reported a series of coordination polymers based on 3TPyP and various metal ions [19,20].…”

Section: Introductionmentioning

confidence: 99%

On the structure of unsolvated free-base 5,10,15,20-tetra(3-pyridyl)porphyrin

Seidel

Goddard

Hoch

et al. 2011

Journal of Molecular Structure

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“…In this case, addition of adamantane carboxylic acid-which is an excellent guest for b-CD-sequesters b-CD and repopulates the double helical conformation. Fujita has previously shown that self-assembled molecular containers promote folding of certain peptides in water [14]. In a previous work, we showed that CB[n ] molecular containers can be used to select a specific member of a 10-component nearly isoenergetic conformational ensemble [8].…”

Section: Introductionmentioning

confidence: 99%

Cucurbit[8]uril Controls the Folding of Cationic Diaryl Ureas in Water

Chakrabarti

Isaacs

2008

Supramolecular Chemistry

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The ability of cucurbit [8]uril (CB[8]) to control the folding of diaryl ureas 1 and 2 in water was investigated. Compounds 1 and 2 contain two ureidyl C-N bonds which can each populate two conformational states resulting in a conformational ensemble comprising at least three states. We find that the presence of CB[8] results in the selective population of the (E,E)-2 conformer by the formation of CB[8]·(E,E)-2 complex at CB[8]:2 stoichiometries of 1: < 1; at higher stoichiometries, an unfolding process takes place during the formation of CB[8]·(Z,Z)-2 2 . In contrast, compound 1 forms the 2:2 complex CB[8] 2 ·(Z,Z)-1 2 over a broad range of CB[8]:2 stoichiometries. The absolute stoichiometries of these complexes were established by diffusion ordered spectroscopic methods (DOSY). The folding of 2 into the (E,E)-2 conformer under the formation of CB[8]·(E,E)-2 is responsive to the presence of guests in its environment. For example, the addition of 8 results in the expulsion of (E,E)-2 from the cavity of CB[8] followed by its unfolding to the thermally preferred mixture of (Z,Z)-and (Z,E)-2 conformers. These results suggest that complexation within synthetic molecular containers-just like their natural counterparts the chaperones-may be an efficient route to control the folding behaviour of non-natural oligomers in aqueous solution.

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Folding of an Ala-Ala-Ala Tripeptide into a β-Turn via Hydrophobic Encapsulation

Cited by 78 publications

References 10 publications

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

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

On the structure of unsolvated free-base 5,10,15,20-tetra(3-pyridyl)porphyrin

Cucurbit[8]uril Controls the Folding of Cationic Diaryl Ureas in Water

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