Propagating structure of Alzheimer’s β-amyloid
            <sub>(10–35)</sub>
            is parallel β-sheet with residues in exact register

Benzinger, Tammie L.S.; Gregory, David; Burkoth, Timothy S.; Miller-Auer, Hélène; Lynn, David G.; Botto, Robert E.; Meredith, Stephen C.

doi:10.1073/pnas.95.23.13407

Cited by 413 publications

(555 citation statements)

References 80 publications

(101 reference statements)

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“…The fibrils observed in our simulations mimic the structural characteristics observed in experiments in that most peptides within a β-sheet in our fibrils are highly parallel to one other [129][130][131] and moderately anti-parallel to peptides within neighboring β-sheets, the intrasheet (C α to C α ) distance is 5.05Å (±0.07) (compared to experimental values of 4.7-4.8Å 11,134,135 ), the inter-sheet (C α to C α ) distance is 7.5Å (±0.5) (compared to experimental values of 8-10Å 11,[134][135][136] ), and our fibrils contain about six β-sheets with each containing multiple peptides 11,[99][100][101] . Finally, we find that when the strength of the hydrophobic interaction between non-polar sidechains is high compared to the strength of the hydrogen bond interaction, amorphous rather than fibrillar aggregates are formed.…”

Section: Discussionsupporting

confidence: 76%

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: Discussionsupporting

confidence: 76%

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Nguyen

Hall

2006

J. Am. Chem. Soc.

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“…In amyloid, a single peptide sequence appears to form either a parallel or an antiparallel strand arrangement (65,(108)(109)(110).…”

Section: Discussionmentioning

confidence: 99%

Solid-State Nuclear Magnetic Resonance Evidence for Parallel and Antiparallel Strand Arrangements in the Membrane-Associated HIV-1 Fusion Peptide

Yang

Weliky

2003

Biochemistry

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The HIV-1 fusion peptide serves as a useful model system for understanding viral/target cell fusion, at least to the lipid-mixing stage. Previous solid-state NMR studies have shown that the membranebound HIV-1 fusion peptide adopts an extended conformation in a lipid mixture close to that of host cells of the virus. In the present study, solid-state NMR REDOR methods were applied for detection of oligomeric strand structure. The samples were prepared under fusogenic conditions and contained equimolar amounts of two peptides, one with selective [ 13 C]carbonyl labeling and the other with selective [ 15 N]amide labeling. In the REDOR measurements, observation of reduced 13 C intensity due to hydrogen-bonded amide 15 N provides strong experimental evidence of oligomer formation by the membrane-associated peptide.Comparison of REDOR spectra on samples that were labeled at different residue positions suggests that there are both parallel and antiparallel arrangements of peptide strands. In the parallel arrangement, interpeptide hydrogen bonding decreases toward the C-terminus, while in the antiparallel arrangement, hydrogen bonds are observed along the entire length of residues which was probed (Gly-5 to Gly-16). For the parallel arrangement, these observations are consistent with the model in which the apolar N-terminal and central regions of the peptides penetrate into the membrane and hydrogen bond with one another while the polar C-terminus of the peptide is outside the membrane and hydrogen bonds with water. These measurements show that, at least at the end state of fusion, the peptide can adopt an oligomeric strand structure.Fusion between the membranes of enveloped viruses such as HIV-1 1 and influenza and the membranes of their target host cells is an essential step in infection (1-4). For these viruses, this process is mediated by integral membrane viral envelope proteins which contain N-terminal ∼20-residue apolar fusion peptide domains. For HIV-1 and influenza, the free fusion peptide has also been shown to be a useful model to understand fusion, at least to the lipid-mixing stage. The free peptide causes fusion of liposomes and erythrocytes, and numerous mutational studies have shown strong correlations between fusion peptide-induced liposome fusion and viral/host cell fusion (5-20). Recent studies suggest that envelope protein regions other than the fusion peptide also interact with membranes and play a role in fusion (21-26).There is a crystal structure of the part of the influenza hemagglutinin envelope protein which lies outside the virus and which contains the fusion peptide (27). This "ectodomain" structure corresponds to a prefusogenic conformation. For both the hemagglutinin and the HIV-1 gp41 envelope proteins, there are also atomic resolution structures of the "soluble ectodomains" which do not contain the fusion peptide (28-34). These structures are believed to correspond to the protein conformations after fusion has occurred and perhaps during fusion as well. In each of these soluble...

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“…Dipolar recoupling with a windowless sequence (DRAWS) is well suited to measuring distances between backbone carbonyl carbons in peptides and proteins [37][38][39][40]. Dipolar couplings of less than 40 Hz between carbonyl 13 C spins have been detected in biopolymers at high magnetic fields [41][42][43][44], attesting to the ability of DRAWS to suppress large CSAs and at the same time detect small dipolar couplings between non-bonded 13 C spins. Fig.…”

Section: Nmr Methods For the Study Of Protein Structure At Biomateriamentioning

confidence: 99%

Solid state NMR studies of molecular recognition at protein–mineral interfaces

Goobes

Stayton

Drobny

2007

Progress in Nuclear Magnetic Resonance Spectroscopy

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Propagating structure of Alzheimer’s β-amyloid _(10–35) is parallel β-sheet with residues in exact register

Cited by 413 publications

References 80 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Solid-State Nuclear Magnetic Resonance Evidence for Parallel and Antiparallel Strand Arrangements in the Membrane-Associated HIV-1 Fusion Peptide

Solid state NMR studies of molecular recognition at protein–mineral interfaces

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Propagating structure of Alzheimer’s β-amyloid (10–35) is parallel β-sheet with residues in exact register

Cited by 413 publications

References 80 publications

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Spontaneous Fibril Formation by Polyalanines; Discontinuous Molecular Dynamics Simulations

Solid-State Nuclear Magnetic Resonance Evidence for Parallel and Antiparallel Strand Arrangements in the Membrane-Associated HIV-1 Fusion Peptide

Solid state NMR studies of molecular recognition at protein–mineral interfaces

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Propagating structure of Alzheimer’s β-amyloid _(10–35) is parallel β-sheet with residues in exact register