The Experts below are selected from a list of 35115 Experts worldwide ranked by ideXlab platform
Christopher M Dobson - One of the best experts on this subject based on the ideXlab platform.
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molecular conformation of a Peptide Fragment of transthyretin in an amyloid fibril
2002Co-Authors: Christopher P Jaroniec, Cait E Macphee, Nathan S Astrof, Christopher M Dobson, Robert G GriffinAbstract:The molecular conformation of Peptide Fragment 105–115 of transthyretin, TTR(105–115), previously shown to form amyloid fibrils in vitro, has been determined by magic-angle spinning solid-state NMR spectroscopy. 13C and 15N linewidth measurements indicate that TTR(105–115) forms a highly ordered structure with each amino acid in a unique environment. 2D 13C-13C and 15N-13C-13C chemical shift correlation experiments, performed on three fibril samples uniformly 13C,15N-labeled in consecutive stretches of 4 aa, allowed the complete sequence-specific backbone and side-chain 13C and 15N resonance assignments to be obtained for residues 105–114. Analysis of the 15N, 13CO, 13Cα, and 13Cβ chemical shifts allowed quantitative predictions to be made for the backbone torsion angles φ and ψ. Furthermore, four backbone 13C–15N distances were determined in two selectively 13C,15N-labeled fibril samples by using rotational-echo double-resonance NMR. The results show that TTR(105–115) adopts an extended β-strand conformation that is similar to that found in the native protein except for substantial differences in the vicinity of the proline residue.
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formation and seeding of amyloid fibrils from wild type hen lysozyme and a Peptide Fragment from the beta domain
2000Co-Authors: Mark R H Krebs, Deborah K Wilkins, Evonne W Chung, Maureen Pitkeathly, Aaron K Chamberlain, Jesus Zurdo, Carol V Robinson, Christopher M DobsonAbstract:Abstract Wild-type hen lysozyme has been converted from its soluble native state into highly organized amyloid fibrils. In order to achieve this conversion, conditions were chosen to promote partial unfolding of the native globular fold and included heating of low-pH solutions and addition of organic solvents. Two Peptides derived from the β-sheet region of hen lysozyme were also found to form fibrils very readily. The properties and morphologies of the amyloid fibrils formed by incubation either of the protein or the Peptides are similar to those produced from the group of proteins associated with clinical amyloidoses. Fibril formation by hen lysozyme was substantially accelerated when aliquots of solutions in which fibrils of either one of the Peptides or the full-length protein had previously formed were added to fresh solutions of the protein, revealing the importance of seeding in the kinetics of fibril formation. These findings support the proposition that the β-domain is of particular significance in the formation of fibrils from the full-length protein and suggest similarities between the species giving rise to fibril formation and the intermediates formed during protein folding.
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formation and seeding of amyloid fibrils from wild type hen lysozyme and a Peptide Fragment from the beta domain
2000Co-Authors: Mark R H Krebs, Deborah K Wilkins, Evonne W Chung, Maureen Pitkeathly, Aaron K Chamberlain, Jesus Zurdo, Carol V Robinson, Christopher M DobsonAbstract:Wild-type hen lysozyme has been converted from its soluble native state into highly organized amyloid fibrils. In order to achieve this conversion, conditions were chosen to promote partial unfolding of the native globular fold and included heating of low-pH solutions and addition of organic solvents. Two Peptides derived from the beta-sheet region of hen lysozyme were also found to form fibrils very readily. The properties and morphologies of the amyloid fibrils formed by incubation either of the protein or the Peptides are similar to those produced from the group of proteins associated with clinical amyloidoses. Fibril formation by hen lysozyme was substantially accelerated when aliquots of solutions in which fibrils of either one of the Peptides or the full-length protein had previously formed were added to fresh solutions of the protein, revealing the importance of seeding in the kinetics of fibril formation. These findings support the proposition that the beta-domain is of particular significance in the formation of fibrils from the full-length protein and suggest similarities between the species giving rise to fibril formation and the intermediates formed during protein folding.
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chemical dissection and reassembly of amyloid fibrils formed by a Peptide Fragment of transthyretin
2000Co-Authors: Cait E Macphee, Christopher M DobsonAbstract:We have examined the chemical dissection and subsequent reassembly of fibrils formed by a ten-residue Peptide to probe the forces that drive the formation of amyloid. The Peptide, TTR(10-19), encompasses the A strand of the inner beta-sheet structure that lines the thyroid hormone binding site of the human plasma protein transthyretin. When dissolved in water under low pH conditions the Peptide readily forms amyloid fibrils. Electron microscopy of these fibrils indicates the presence of long (>1000 nm) rigid structures of uniform diameter (approximately 14 nm). Addition of urea (3 M) to preformed fibrils disrupts these rigid structures. The partially disrupted fibrils form flexible ribbon-like arrays, which are composed of a number of clearly visible protofilaments (3-4 nm diameter). These protofilaments are highly stable, and resist denaturation in 6 M urea at 75 degrees C over a period of hours. High concentrations (>50%, v/v) of 2,2,2-trifluoroethanol also dissociate TTR(10-19) fibrils to the constituent protofilaments, but these slowly dissociate to monomeric, soluble Peptides with extensive alpha-helical structure. Dilution of the denaturant or co-solvent at the stage when dissociation to protofilaments has occurred results in the efficient reassembly of fibrils. These results indicate that assembly of fibrils from protofilaments involves relatively weak and predominantly hydrophobic interactions, whereas assembly of Peptides into protofilaments involves both electrostatic and hydrophobic forces, resulting in a highly stable and compact structures.
Gerhard Hummer - One of the best experts on this subject based on the ideXlab platform.
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position dependent diffusion coefficients and free energies from bayesian analysis of equilibrium and replica molecular dynamics simulations
2005Co-Authors: Gerhard HummerAbstract:Bayesian inference is used to obtain self-consistent estimates of free energies and position-dependent diffusion coefficients along complex reaction coordinates from molecular dynamics simulation trajectories. Effectively, exact solutions for the dynamics of a diffusive model are matched globally to the observed molecular dynamics data. The approach is first tested for a simple one-dimensional diffusion model, and then applied to the dihedral-angle dynamics of a Peptide Fragment dissolved in water. Both long equilibrium molecular dynamics simulations and short, appropriately initialized, replica simulations are used to sample the short-time dynamics of the Peptide–water system. In both cases, accurate estimates of free energies and diffusion coefficients are obtained.
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coarse molecular dynamics of a Peptide Fragment free energy kinetics and long time dynamics computations
2003Co-Authors: Gerhard Hummer, Ioannis G KevrekidisAbstract:We present a “coarse molecular dynamics” approach and apply it to studying the kinetics and thermodynamics of a Peptide Fragment dissolved in water. Short bursts of appropriately initialized simulations are used to infer the deterministic and stochastic components of the Peptide motion parametrized by an appropriate set of coarse variables. Techniques from traditional numerical analysis (Newton–Raphson, coarse projective integration) are thus enabled; these techniques help analyze important features of the free-energy landscape (coarse transition states, eigenvalues and eigenvectors, transition rates, etc.). Reverse integration of coarse variables backward in time can assist escape from free energy minima and trace low-dimensional free energy surfaces. To illustrate the coarse molecular dynamics approach, we combine multiple short (0.5 ps) replica simulations to map the free energy surface of the “alanine diPeptide” in water, and to determine the ∼1/(1000 ps) rate of interconversion between the two stable configurational basins corresponding to the α-helical and extended minima.
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coarse molecular dynamics of a Peptide Fragment free energy kinetics and long time dynamics computations
2002Co-Authors: Gerhard Hummer, Ioannis G KevrekidisAbstract:We present a ``coarse molecular dynamics'' approach and apply it to studying the kinetics and thermodynamics of a Peptide Fragment dissolved in water. Short bursts of appropriately initialized simulations are used to infer the deterministic and stochastic components of the Peptide motion parametrized by an appropriate set of coarse variables. Techniques from traditional numerical analysis (Newton-Raphson, coarse projective integration) are thus enabled; these techniques help analyze important features of the free-energy landscape (coarse transition states, eigenvalues and eigenvectors, transition rates, etc.). Reverse integration of (irreversible) expected coarse variables backward in time can assist escape from free energy minima and trace low-dimensional free energy surfaces. To illustrate the ``coarse molecular dynamics'' approach, we combine multiple short (0.5-ps) replica simulations to map the free energy surface of the ``alanine diPeptide'' in water, and to determine the ~ 1/(1000 ps) rate of interconversion between the two stable configurational basins corresponding to the alpha-helical and extended minima.
Valeria Castelletto - One of the best experts on this subject based on the ideXlab platform.
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influence of the solvent on the self assembly of a modified amyloid beta Peptide Fragment i morphological investigation
2009Co-Authors: Valeria Castelletto, Peter J F Harris, Ian W. Hamley, Ulf Olsson, Nicholas D. SpencerAbstract:The solvent-induced transition between self-assembled structures formed by the Peptide AAKLVFF is studied via electron microscopy, light scattering, and spectroscopic techniques. The Peptide is based on a core Fragment of the amyloid β-Peptide, KLVFF, extended by two alanine residues. AAKLVFF exhibits distinct structures of twisted fibrils in water or nanotubes in methanol. For intermediate water/methanol compositions, these structures are disrupted and replaced by wide filamentous tapes that appear to be lateral aggregates of thin protofilaments. The orientation of the β-strands in the twisted tapes or nanotubes can be deduced from X-ray diffraction on aligned stalks, as well as FT-IR experiments in transmission compared to attenuated total reflection. Strands are aligned perpendicular to the axis of the twisted fibrils or the nanotubes. The results are interpreted in light of recent results on the effect of competitive hydrogen bonding upon self-assembly in soft materials in water/methanol mixtures.
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influence of the solvent on the self assembly of a modified amyloid beta Peptide Fragment i morphological investigation
2009Co-Authors: Valeria Castelletto, Peter J F Harris, Ian W. Hamley, Ulf Olsson, Nick J SpencerAbstract:The solvent-induced transition between self-assembled structures formed by the Peptide AAKLVFF is studied via electron microscopy, light scattering, and spectroscopic techniques. The Peptide is based on a core Fragment of the amyloid beta-Peptide, KLVFF, extended by two alanine residues. AAKLVFF exhibits distinct structures of twisted fibrils in water or nanotubes in methanol. For intermediate water/methanol compositions, these structures are disrupted and replaced by wide filamentous tapes that appear to be lateral aggregates of thin protofilaments. The orientation of the beta-strands in the twisted tapes or nanotubes can be deduced from X-ray diffraction on aligned stalks, as well as FT-IR experiments in transmission compared to attenuated total reflection. Strands are aligned perpendicular to the axis of the twisted fibrils or the nanotubes. The results are interpreted in light of recent results on the effect of competitive hydrogen bonding upon self-assembly in soft materials in water/methanol mixtures.
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Helical-ribbon formation by a beta-amino acid modified amyloid beta-Peptide Fragment.
2009Co-Authors: Valeria Castelletto, Rohan A. Hule, Ian W. Hamley, Darrin J PochanAbstract:An addition to the family: The introduction of beta-amino acid residues into a modified amyloid beta Peptide Fragment resulted in well-defined helical nanoribbons (see cryo-TEM image) comprising beta strands mainly oriented perpendicular to the ribbon axis. The nanoribbons order into a flow-aligning nematic phase at higher concentration. The beta-strand nanoribbon structure is an addition to the known set of secondary structures adopted by beta-Peptides.
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self assembly and hydrogelation of an amyloid Peptide Fragment
2008Co-Authors: Marta J Krysmann, Rohan A. Hule, Ian W. Hamley, Valeria Castelletto, Antonios Kelarakis, Darrin J PochanAbstract:The self-assembly of a Fragment of the amyloid β Peptide that has been shown to be critical in amyloid fibrillization has been studied in aqueous solution. There are conflicting reports in the literature on the fibrillization of Aβ (16–20), i.e., KLVFF, and our results shed light on this. In dilute solution, self-assembly of NH2−KLVFF−COOH is strongly influenced by aromatic interactions between phenylalanine units, as revealed by UV spectroscopy and circular dichroism. Fourier transform infrared (FTIR) spectroscopy reveals β-sheet features in spectra taken for more concentrated solutions and also dried films. X-ray diffraction and cryo-transmission electron microscopy (cryo-TEM) provide further support for β-sheet amyloid fibril formation. A comparison of cryo-TEM images with those from conventional dried and negatively stained TEM specimens highlights the pronounced effects of sample preparation on the morphology. A comparison of FTIR data for samples in solution and dried samples also highlights the str...
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self assembly and hydrogelation of an amyloid Peptide Fragment
2008Co-Authors: Marta J Krysmann, Rohan A. Hule, Ian W. Hamley, Valeria Castelletto, Antonios Kelarakis, Darrin J PochanAbstract:The self-assembly of a Fragment of the amyloid beta Peptide that has been shown to be critical in amyloid fibrillization has been studied in aqueous solution. There are conflicting reports in the literature on the fibrillization of Abeta (16-20), i.e., KLVFF, and our results shed light on this. In dilute solution, self-assembly of NH 2-KLVFF-COOH is strongly influenced by aromatic interactions between phenylalanine units, as revealed by UV spectroscopy and circular dichroism. Fourier transform infrared (FTIR) spectroscopy reveals beta-sheet features in spectra taken for more concentrated solutions and also dried films. X-ray diffraction and cryo-transmission electron microscopy (cryo-TEM) provide further support for beta-sheet amyloid fibril formation. A comparison of cryo-TEM images with those from conventional dried and negatively stained TEM specimens highlights the pronounced effects of sample preparation on the morphology. A comparison of FTIR data for samples in solution and dried samples also highlights the strong effect of drying on the self-assembled structure. In more concentrated phosphate-buffered saline (PBS) solution, gelation of NH 2-KLVFF-COOH is observed. This is believed to be caused by screening of the electrostatic charge on the Peptide, which enables beta sheets to aggregate into a fibrillar gel network. The rheology of the hydrogel is probed, and the structure is investigated by light scattering and small-angle X-ray scattering.
Darrin J Pochan - One of the best experts on this subject based on the ideXlab platform.
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Helical-ribbon formation by a beta-amino acid modified amyloid beta-Peptide Fragment.
2009Co-Authors: Valeria Castelletto, Rohan A. Hule, Ian W. Hamley, Darrin J PochanAbstract:An addition to the family: The introduction of beta-amino acid residues into a modified amyloid beta Peptide Fragment resulted in well-defined helical nanoribbons (see cryo-TEM image) comprising beta strands mainly oriented perpendicular to the ribbon axis. The nanoribbons order into a flow-aligning nematic phase at higher concentration. The beta-strand nanoribbon structure is an addition to the known set of secondary structures adopted by beta-Peptides.
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self assembly and hydrogelation of an amyloid Peptide Fragment
2008Co-Authors: Marta J Krysmann, Rohan A. Hule, Ian W. Hamley, Valeria Castelletto, Antonios Kelarakis, Darrin J PochanAbstract:The self-assembly of a Fragment of the amyloid β Peptide that has been shown to be critical in amyloid fibrillization has been studied in aqueous solution. There are conflicting reports in the literature on the fibrillization of Aβ (16–20), i.e., KLVFF, and our results shed light on this. In dilute solution, self-assembly of NH2−KLVFF−COOH is strongly influenced by aromatic interactions between phenylalanine units, as revealed by UV spectroscopy and circular dichroism. Fourier transform infrared (FTIR) spectroscopy reveals β-sheet features in spectra taken for more concentrated solutions and also dried films. X-ray diffraction and cryo-transmission electron microscopy (cryo-TEM) provide further support for β-sheet amyloid fibril formation. A comparison of cryo-TEM images with those from conventional dried and negatively stained TEM specimens highlights the pronounced effects of sample preparation on the morphology. A comparison of FTIR data for samples in solution and dried samples also highlights the str...
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self assembly and hydrogelation of an amyloid Peptide Fragment
2008Co-Authors: Marta J Krysmann, Rohan A. Hule, Ian W. Hamley, Valeria Castelletto, Antonios Kelarakis, Darrin J PochanAbstract:The self-assembly of a Fragment of the amyloid beta Peptide that has been shown to be critical in amyloid fibrillization has been studied in aqueous solution. There are conflicting reports in the literature on the fibrillization of Abeta (16-20), i.e., KLVFF, and our results shed light on this. In dilute solution, self-assembly of NH 2-KLVFF-COOH is strongly influenced by aromatic interactions between phenylalanine units, as revealed by UV spectroscopy and circular dichroism. Fourier transform infrared (FTIR) spectroscopy reveals beta-sheet features in spectra taken for more concentrated solutions and also dried films. X-ray diffraction and cryo-transmission electron microscopy (cryo-TEM) provide further support for beta-sheet amyloid fibril formation. A comparison of cryo-TEM images with those from conventional dried and negatively stained TEM specimens highlights the pronounced effects of sample preparation on the morphology. A comparison of FTIR data for samples in solution and dried samples also highlights the strong effect of drying on the self-assembled structure. In more concentrated phosphate-buffered saline (PBS) solution, gelation of NH 2-KLVFF-COOH is observed. This is believed to be caused by screening of the electrostatic charge on the Peptide, which enables beta sheets to aggregate into a fibrillar gel network. The rheology of the hydrogel is probed, and the structure is investigated by light scattering and small-angle X-ray scattering.
Ian W. Hamley - One of the best experts on this subject based on the ideXlab platform.
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influence of the solvent on the self assembly of a modified amyloid beta Peptide Fragment i morphological investigation
2009Co-Authors: Valeria Castelletto, Peter J F Harris, Ian W. Hamley, Ulf Olsson, Nicholas D. SpencerAbstract:The solvent-induced transition between self-assembled structures formed by the Peptide AAKLVFF is studied via electron microscopy, light scattering, and spectroscopic techniques. The Peptide is based on a core Fragment of the amyloid β-Peptide, KLVFF, extended by two alanine residues. AAKLVFF exhibits distinct structures of twisted fibrils in water or nanotubes in methanol. For intermediate water/methanol compositions, these structures are disrupted and replaced by wide filamentous tapes that appear to be lateral aggregates of thin protofilaments. The orientation of the β-strands in the twisted tapes or nanotubes can be deduced from X-ray diffraction on aligned stalks, as well as FT-IR experiments in transmission compared to attenuated total reflection. Strands are aligned perpendicular to the axis of the twisted fibrils or the nanotubes. The results are interpreted in light of recent results on the effect of competitive hydrogen bonding upon self-assembly in soft materials in water/methanol mixtures.
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influence of the solvent on the self assembly of a modified amyloid beta Peptide Fragment i morphological investigation
2009Co-Authors: Valeria Castelletto, Peter J F Harris, Ian W. Hamley, Ulf Olsson, Nick J SpencerAbstract:The solvent-induced transition between self-assembled structures formed by the Peptide AAKLVFF is studied via electron microscopy, light scattering, and spectroscopic techniques. The Peptide is based on a core Fragment of the amyloid beta-Peptide, KLVFF, extended by two alanine residues. AAKLVFF exhibits distinct structures of twisted fibrils in water or nanotubes in methanol. For intermediate water/methanol compositions, these structures are disrupted and replaced by wide filamentous tapes that appear to be lateral aggregates of thin protofilaments. The orientation of the beta-strands in the twisted tapes or nanotubes can be deduced from X-ray diffraction on aligned stalks, as well as FT-IR experiments in transmission compared to attenuated total reflection. Strands are aligned perpendicular to the axis of the twisted fibrils or the nanotubes. The results are interpreted in light of recent results on the effect of competitive hydrogen bonding upon self-assembly in soft materials in water/methanol mixtures.
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Helical-ribbon formation by a beta-amino acid modified amyloid beta-Peptide Fragment.
2009Co-Authors: Valeria Castelletto, Rohan A. Hule, Ian W. Hamley, Darrin J PochanAbstract:An addition to the family: The introduction of beta-amino acid residues into a modified amyloid beta Peptide Fragment resulted in well-defined helical nanoribbons (see cryo-TEM image) comprising beta strands mainly oriented perpendicular to the ribbon axis. The nanoribbons order into a flow-aligning nematic phase at higher concentration. The beta-strand nanoribbon structure is an addition to the known set of secondary structures adopted by beta-Peptides.
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self assembly and hydrogelation of an amyloid Peptide Fragment
2008Co-Authors: Marta J Krysmann, Rohan A. Hule, Ian W. Hamley, Valeria Castelletto, Antonios Kelarakis, Darrin J PochanAbstract:The self-assembly of a Fragment of the amyloid β Peptide that has been shown to be critical in amyloid fibrillization has been studied in aqueous solution. There are conflicting reports in the literature on the fibrillization of Aβ (16–20), i.e., KLVFF, and our results shed light on this. In dilute solution, self-assembly of NH2−KLVFF−COOH is strongly influenced by aromatic interactions between phenylalanine units, as revealed by UV spectroscopy and circular dichroism. Fourier transform infrared (FTIR) spectroscopy reveals β-sheet features in spectra taken for more concentrated solutions and also dried films. X-ray diffraction and cryo-transmission electron microscopy (cryo-TEM) provide further support for β-sheet amyloid fibril formation. A comparison of cryo-TEM images with those from conventional dried and negatively stained TEM specimens highlights the pronounced effects of sample preparation on the morphology. A comparison of FTIR data for samples in solution and dried samples also highlights the str...
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self assembly and hydrogelation of an amyloid Peptide Fragment
2008Co-Authors: Marta J Krysmann, Rohan A. Hule, Ian W. Hamley, Valeria Castelletto, Antonios Kelarakis, Darrin J PochanAbstract:The self-assembly of a Fragment of the amyloid beta Peptide that has been shown to be critical in amyloid fibrillization has been studied in aqueous solution. There are conflicting reports in the literature on the fibrillization of Abeta (16-20), i.e., KLVFF, and our results shed light on this. In dilute solution, self-assembly of NH 2-KLVFF-COOH is strongly influenced by aromatic interactions between phenylalanine units, as revealed by UV spectroscopy and circular dichroism. Fourier transform infrared (FTIR) spectroscopy reveals beta-sheet features in spectra taken for more concentrated solutions and also dried films. X-ray diffraction and cryo-transmission electron microscopy (cryo-TEM) provide further support for beta-sheet amyloid fibril formation. A comparison of cryo-TEM images with those from conventional dried and negatively stained TEM specimens highlights the pronounced effects of sample preparation on the morphology. A comparison of FTIR data for samples in solution and dried samples also highlights the strong effect of drying on the self-assembled structure. In more concentrated phosphate-buffered saline (PBS) solution, gelation of NH 2-KLVFF-COOH is observed. This is believed to be caused by screening of the electrostatic charge on the Peptide, which enables beta sheets to aggregate into a fibrillar gel network. The rheology of the hydrogel is probed, and the structure is investigated by light scattering and small-angle X-ray scattering.