Structure of the β-Amyloid(10-35) Fibril

Burkoth, Timothy S.; Benzinger, Tammie L.S.; Urban, Volker S.; Morgan, David M. L.; Gregory, David; Thiyagarajan, P.; Botto, Robert E.; Meredith, and Stephen C.; Lynn, David G.

doi:10.1021/ja000645z

Cited by 230 publications

(285 citation statements)

References 23 publications

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“…Perhaps, the orientation of peptides in beta-sheets depends on the peptide length. This is known to be the case for Aβ where Aβ(34-42) 132 and Aβ (16)(17)(18)(19)(20)(21)(22) 133 form antiparallel beta sheets while Aβ(10-35) 100 and Aβ(1-40) 130 form parallel beta sheets. The dependency of the peptide orientation in β-sheets specifically and the formation of β-sheets or fibrils in general on the peptide length will be explored in a future publication.…”

Section: Fibril Structurementioning

confidence: 90%

“…The peptide concentrations for the 48-peptide system are c ≡ N/N A V ≈ 0.5, 1, 2.5, 5, 10, and 20mM where N A is Avogadro's number. Though our system is small compared with real fibrils (actually protofilaments) which tend to contain four to six β-sheets with 1000 or more peptides per sheet 11,[99][100][101] , it is quite large compared with the few peptides simulated in other studies 32,33,102,103,34 . Hopefully this is sufficient to provide a foundation for the basic understanding of fibril formation in larger systems.…”

Section: Discontinuous Molecular Dynamicsmentioning

confidence: 97%

“…Our fibrils contain the same number of β-sheets as in real fibrils, four to six sheets 11,[99][100][101] . Snapshots of fibrils formed for different system sizes are shown in Figure 10.…”

Section: Fibril Structurementioning

confidence: 99%

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Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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Fibrillary protein aggregates rich in β-sheet structure have been implicated in the pathology of several neurodegenerative diseases. In this work, we investigate the formation of fibrils by performing discontinuous molecular dynamics simulations on systems containing 12 to 96 model Ac-KA 14 K-NH 2 peptides using our newly-developed off-lattice, implicit-solvent, intermediateresolution model, PRIME. We find that at a low concentration, random-coil peptides assemble into α-helices at low temperatures. At intermediate concentrations, random-coil peptides assemble into α-helices at low temperatures and large β-sheet structures at high temperatures. At high concentrations, the system forms β-sheets over a wide range of temperatures. These assemble into fibrils above a critical temperature which decreases with concentration and exceeds the isolated peptide's folding temperature. At very high temperatures and all concentrations, the system is in a random-coil state. All of these results are in good qualitative agreement with those by Blondelle and coworkers on Ac-KA 14 K-NH 2 peptides. The fibrils observed in our simulations mimic the structural characteristics observed in experiments in terms of the number of sheets formed, the values of the intra-and inter-sheet separations, and the parallel peptide arrangement within each β-sheet. Finally, we find that when the strength of the hydrophobic interaction between non-polar sidechains is high compared to the strength of hydrogen bonding, amorphous aggregates, rather than fibrillar aggregates, are formed.

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Section: Fibril Structurementioning

confidence: 90%

Section: Discontinuous Molecular Dynamicsmentioning

confidence: 97%

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Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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“…4 In the past, several Ab fibril structure models have been suggested. These are based on MAS solidstate NMR experiments, [5][6][7][8][9][10][11] and cryo-electron microscopic image reconstructions. 12 Even though there is some controversy concerning the conformational space that Ab fibrils can adopt, all published models, including the 2-fold 7,10 and 3-fold 9 symmetric Ab 1-40 fibril structure suggested by Tycko, and Bertini and co-workers, agree on the basic building block which involves a b-sheet (b1, residues 12-24), a turn, and a second b-sheet (b2, residues [28][29][30][31][32][33][34][35][36][37][38][39][40].…”

mentioning

confidence: 99%

Hydrogen bonding involving side chain exchangeable groups stabilizes amyloid quarternary structure

Agarwal

Linser

Dasari

et al. 2013

Phys. Chem. Chem. Phys.

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The amyloid b-peptide (Ab) is the major structural component of amyloid fibrils in the plaques of brains of Alzheimer's disease patients. Numerous studies have addressed important aspects of secondary and tertiary structure of fibrils. In electron microscopic images, fibrils often bundle together. The mechanisms which drive the association of protofilaments into bundles of fibrils are not known. We show here that amino acid side chain exchangeable groups like e.g. histidines can provide useful restraints to determine the quarternary assembly of an amyloid fibril. Exchangeable protons are only observable if a side chain hydrogen bond is formed and the respective protons are protected from exchange. The method relies on deuteration of the Ab peptide. Exchangeable deuterons are substituted with protons, before fibril formation is initiated.Alzheimer's disease (AD) is a slowly progressive neurological disorder which is associated with memory loss, cognitive impairment and finally dementia and death. The amyloid b-peptide (Ab) is the major structural component of amyloid fibrils in the plaques of brains of Alzheimer's disease patients. Ab is a cleavage product resulting from Alzheimer Precursor Protein (APP) processing. 1 The g-secretase cut yields Ab fragments of different lengths of which Ab40 and Ab42 are most abundant. 2,3 In vitro, the Ab peptide aggregates over time into oligomers and fibrillar structures. 4 In the past, several Ab fibril structure models have been suggested. These are based on MAS solidstate NMR experiments, 5-11 and cryo-electron microscopic image reconstructions. 12 Even though there is some controversy concerning the conformational space that Ab fibrils can adopt, all published models, including the 2-fold 7,10 and 3-fold 9 symmetric Ab 1-40 fibril structure suggested by Tycko, and Bertini and co-workers, agree on the basic building block which involves a b-sheet (b1, residues 12-24), a turn, and a second b-sheet (b2, residues 28-40). Biophysical studies indicate a certain degree of conformational plasticity for the N-terminal b-sheet. 13,14 Whereas b2 is present in all the studies, b1 can be truncated or does not adopt a regular b-sheet structure. Depending on the preparation conditions, amide protons in the region of the peptide where the first b-strand is expected show differential H/D protection factors. 13 Similarly, a certain degree of conformational variability in the N-terminus is suggested using cryo-electron microscopy. 14 In all structural models, Ab peptides are arranged in a parallel fashion. An antiparallel arrangement is only observed for the Iowa mutant Ab-D23N, 15 and for truncated forms of the peptide such as Ab [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] . 16 The fibril structure is stabilized in particular by hydrogen bonding interactions. Therefore, observation of exchangeable and titratable groups is of particular interest to identify hydrogen bonding patterns. We and others could show in the past that high resolution proton spectra can be obtained for...

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“…Such studies should provide fundamental insight on a structural motif that is very common in proteins and in protein aggregates associated with human diseases. 14 …”

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confidence: 99%

Thermodynamic Analysis of Autonomous Parallel β-Sheet Formation in Water

2006

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We report the first thermodynamic analysis of parallel β-sheet formation in a model system that folds in aqueous solution. NMR chemical shifts were used to determine β-sheet population, and van't Hoff analysis provided thermodynamic parameters. Our approach relies upon the D-prolyl-1,1-dimethyl-1,2-diaminoethane unit to promote parallel β-sheet formation between attached peptide strands. The development of a macrocyclic reference molecule to provide chemical shift data for the fully folded state was crucial to the quantitative analysis.Protein folding patterns are dominated by two regular substructures, α-helix and β-sheet. The origins of conformational stability for these secondary structures, a subject of intense interest, can be explored with peptides that form a helix or sheet in the absense of a tertiary context. Design rules for medium-length peptides that form autonomous α-helices in aqueous solution were delineated in the 1980s, 1 and comparable achievements for autonomous antiparallel β-sheets were reported in the 1990s. 2 In both cases, the development of strategies for determining folded populations has allowed thermodynamic analysis of secondary structure formation. 3 An autonomously folding parallel β-sheet (in contrast to an autonomous antiparallel β-sheet or α-helix) cannot be created exclusively from α-amino acid residues because the N-terminus of one strand in a parallel β-sheet does not lie near the C-terminus of a neighboring strand.*gellman@chem.wisc.edu. Supporting Information Available: Information concerning the synthesis of 3; chemical shift and NOE information on 1, 2, and 3; TFE titration data for 3 and the van't Hoff analysis of folding. This material is available free of charge via the Internet at http://pubs.acs.org. Many groups have explored non-peptide units that promote parallel sheet interactions, most commonly by linking C-termini with a short turn-forming diamine. 4 We have previously reported that the D-prolyl-1,1-dimethyl-1,2-diaminoethane (D-Pro-DADME) supports formation of a two-stranded parallel β-sheet in water, as indicated by 2D NMR data. 5 Here we show that the thermodynamics of parallel β-sheet formation can be evaluated in such a model system. This accomplishment provides a foundation for exploring sequence-stability relationships in the parallel β-sheet structural manifold, which would fill a significant gap in our understanding of proteins and protein aggregates. NIH Public AccessNMR chemical shifts provide the most reliable insight on folded populations among antiparallel β-sheet model systems, 3,6 and we therefore aimed for a chemical shift-based analysis of parallel β-sheet folding. Most autonomous helix or sheet systems are not fully folded under accessible conditions; therefore, chemical shifts for such systems are populationweighted averages of the contributions from the limiting folded and unfolded states. To analyze 1 we have built upon the strategy previously developed for antiparallel β-sheets by constructing model compounds intended to provid...

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Structure of the β-Amyloid₍₁₀_-₃₅₎ Fibril

Cited by 230 publications

References 23 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Hydrogen bonding involving side chain exchangeable groups stabilizes amyloid quarternary structure

Thermodynamic Analysis of Autonomous Parallel β-Sheet Formation in Water

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