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Mark S Searle - One of the best experts on this subject based on the ideXlab platform.
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folding of a Beta hairpin peptide derived from the n terminus of ubiquitin conformational preferences of Beta turn residues dictate non native Beta Strand interactions
FEBS Journal, 2000Co-Authors: Muriel Jourdan, Sam Griffithsjones, Mark S SearleAbstract:The role of the non-native Beta-turn sequence (NPDG) in nucleating the folding of a Beta-hairpin peptide derived from the N-terminus of ubiquitin, has been examined by NMR and CD spectroscopy. The NPDG sequence, while representing a common two-residue type I turn sequence in proteins, folds to give a G1-bulged type I turn in the context of a Beta-hairpin peptide, to the exclusion of other possible conformations. The turn conformation results in misalignment of the two Beta Strands and a Beta hairpin with non-native side chain interactions. A truncated 12-residue analogue of the hairpin, in which the majority of residues in the N-terminal Beta Strand have been deleted, shows some weak propensity to fold into a G-bulged type I turn conformation in the absence of interStrand stabilizing interactions. The NPDG turn sequence pays some of the entropic cost in initiating folding allowing interStrand interactions, which in this case arise from the non-native pairing of residue side chains, to stabilize a significant population of the folded state. Examination of the relative abundance of the Pro-Asp type I turn, with G in the +B1 position, vs. the type I G-bulged turn PXG, in a database of high resolution structures, reveals 48 instances of PXG bulged turns for which X = Asp is by far the most common residue with 20 occurrences. Strikingly, there are no examples of a type I PD turn with G at the +B1 position, in good agreement with our experimental observations that the PDG G-bulged turn is populated preferentially in solution.
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dissecting the stability of a Beta hairpin peptide that folds in water nmr and molecular dynamics analysis of the Beta turn and Beta Strand contributions to folding
Journal of Molecular Biology, 1999Co-Authors: Sam Griffithsjones, Allister J Maynard, Mark S SearleAbstract:NMR studies of the folding and conformational properties of a Beta-hairpin peptide, several peptide fragments of the hairpin, and sequence-modified analogues, have enabled the various contributions to Beta-hairpin stability in water to be dissected. Temperature and pH-induced unfolding studies indicate that the folding-unfolding equilibrium approximates to a two-state model. The hairpin is highly resistant to denaturation and is still significantly folded in 7 M urea at 298 K. Thermodynamic analysis shows the hairpin to fold in water with a significant change in heat capacity, however, DeltaCp degrees in 7 M urea is reduced. V/Y-->A mutations on one Strand of the hairpin reduce folding to <10 %, consistent with a hydrophobic stabilisation model. We show that in a truncated peptide (residues 6-16) lacking the hydrophobic residues on one Beta-Strand, the type I' Asn-Gly turn in the sequence SINGKK is significantly populated in water in the absence of interStrand hydrophobic contacts. Unrestrained molecular dynamics simulations of unfolding, using an explicit solvation model, show that the conformation of the NG turn persists for longer than the AG analogue, which has a much lower propensity for type I' turn formation from a data base analysis of preferred turns. The origin of the high stability of the Asn-Gly turn is not entirely clear; data base analysis of 66 NG turns, together with molecular dynamics simulations, reveals no participation of the Asn side-chain in turn-stabilising interactions with the peptide backbone. However, hydration analysis of the molecular dynamics simulations reveals a pocket of "high density" water bridging between the Asn side-chain and peptide main-chain that suggests solvent-mediated interactions may play an important role in modulating phi,psi propensities in the NG turn region.
Darrin J Pochan - One of the best experts on this subject based on the ideXlab platform.
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the peptide hormone glucagon forms amyloid fibrils with two coexisting Beta Strand conformations
Nature Structural & Molecular Biology, 2019Co-Authors: Martin D Gelenter, Katelyn J Smith, Shuyu Liao, Venkata S Mandala, Aurelio J Dregni, Matthew S Lamm, Yu Tian, Darrin J PochanAbstract:Glucagon and insulin maintain blood glucose homeostasis and are used to treat hypoglycemia and hyperglycemia, respectively, in patients with diabetes. Whereas insulin is stable for weeks in its solution formulation, glucagon fibrillizes rapidly at the acidic pH required for solubility and is therefore formulated as a lyophilized powder that is reconstituted in an acidic solution immediately before use. Here we use solid-state NMR to determine the atomic-resolution structure of fibrils of synthetic human glucagon grown at pharmaceutically relevant low pH. Unexpectedly, two sets of chemical shifts are observed, indicating the coexistence of two β-Strand conformations. The two conformations have distinct water accessibilities and intermolecular contacts, indicating that they alternate and hydrogen bond in an antiparallel fashion along the fibril axis. Two antiparallel β-sheets assemble with symmetric homodimer cross sections. This amyloid structure is stabilized by numerous aromatic, cation-π, polar and hydrophobic interactions, suggesting mutagenesis approaches to inhibit fibrillization could improve this important drug.
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Helical-ribbon formation by a Beta-amino acid modified amyloid Beta-peptide fragment.
Angewandte Chemie (International ed. in English), 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.
David P. Fairlie - One of the best experts on this subject based on the ideXlab platform.
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A cyclic Beta-Strand tripeptide with an alpha-helix like CD spectrum
Organic Letters, 2009Co-Authors: Russell W Driver, Giovanni Abbenante, Huy N Hoang, David P. FairlieAbstract:A protein alpha-helix is defined by 3.6 amino acids per turn. Cyclization of the tripeptide Alanine-Leucine-Glutamate through a side chain to the N-terminus lactam bond produces cyclo-(1,3)-[ALE]-NH(2) which displays a circular dichroism spectrum typical of an alpha-helix backbone. However, proton NMR spectra show a novel cyclic peptide featuring two non-hydrogen-bonded antiparallel Beta-Strands connected by an Ala-Leu cis-amide bond. This example highlights that the common practice of characterizing alpha-helices by CD spectra alone can be misleading.
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Mimetics of the peptide Beta-Strand.
Mini-reviews in Medicinal Chemistry, 2002Co-Authors: Matthew P. Glenn, David P. FairlieAbstract:Bioactive structures of peptides represent important clues for drug discovery and development although peptides themselves have substantial limitations as drugs. One promising approach to overcoming the limitations of peptides is to progressively replace amide bonds in peptides with non-peptidic constraints that bring drug-like properties like stability and bioavailability to the molecules. These constraints can also be used to mould molecules into shapes which mimic key elements of protein secondary structure that confer bioactivity to protein surfaces. Preorganizing a molecule into the shape recognized by a receptor results in high affinity binding though a considerable entropy saving and is an effective approach to engineering highly bioactive drug leads. One peptide structure, the extended Beta Strand, has only recently been identified as a fundamental recognition element in physiological processes. Relatively few molecules have been described as constrained mimics of extended peptide conformations. We now summarize some approaches to mimicking peptide Beta Strands, and illustrate these with examples of bioactive, stable and bioavailable molecules that are conformationally biased to mimic the extended peptide Beta Strand.
Sam Griffithsjones - One of the best experts on this subject based on the ideXlab platform.
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folding of a Beta hairpin peptide derived from the n terminus of ubiquitin conformational preferences of Beta turn residues dictate non native Beta Strand interactions
FEBS Journal, 2000Co-Authors: Muriel Jourdan, Sam Griffithsjones, Mark S SearleAbstract:The role of the non-native Beta-turn sequence (NPDG) in nucleating the folding of a Beta-hairpin peptide derived from the N-terminus of ubiquitin, has been examined by NMR and CD spectroscopy. The NPDG sequence, while representing a common two-residue type I turn sequence in proteins, folds to give a G1-bulged type I turn in the context of a Beta-hairpin peptide, to the exclusion of other possible conformations. The turn conformation results in misalignment of the two Beta Strands and a Beta hairpin with non-native side chain interactions. A truncated 12-residue analogue of the hairpin, in which the majority of residues in the N-terminal Beta Strand have been deleted, shows some weak propensity to fold into a G-bulged type I turn conformation in the absence of interStrand stabilizing interactions. The NPDG turn sequence pays some of the entropic cost in initiating folding allowing interStrand interactions, which in this case arise from the non-native pairing of residue side chains, to stabilize a significant population of the folded state. Examination of the relative abundance of the Pro-Asp type I turn, with G in the +B1 position, vs. the type I G-bulged turn PXG, in a database of high resolution structures, reveals 48 instances of PXG bulged turns for which X = Asp is by far the most common residue with 20 occurrences. Strikingly, there are no examples of a type I PD turn with G at the +B1 position, in good agreement with our experimental observations that the PDG G-bulged turn is populated preferentially in solution.
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dissecting the stability of a Beta hairpin peptide that folds in water nmr and molecular dynamics analysis of the Beta turn and Beta Strand contributions to folding
Journal of Molecular Biology, 1999Co-Authors: Sam Griffithsjones, Allister J Maynard, Mark S SearleAbstract:NMR studies of the folding and conformational properties of a Beta-hairpin peptide, several peptide fragments of the hairpin, and sequence-modified analogues, have enabled the various contributions to Beta-hairpin stability in water to be dissected. Temperature and pH-induced unfolding studies indicate that the folding-unfolding equilibrium approximates to a two-state model. The hairpin is highly resistant to denaturation and is still significantly folded in 7 M urea at 298 K. Thermodynamic analysis shows the hairpin to fold in water with a significant change in heat capacity, however, DeltaCp degrees in 7 M urea is reduced. V/Y-->A mutations on one Strand of the hairpin reduce folding to <10 %, consistent with a hydrophobic stabilisation model. We show that in a truncated peptide (residues 6-16) lacking the hydrophobic residues on one Beta-Strand, the type I' Asn-Gly turn in the sequence SINGKK is significantly populated in water in the absence of interStrand hydrophobic contacts. Unrestrained molecular dynamics simulations of unfolding, using an explicit solvation model, show that the conformation of the NG turn persists for longer than the AG analogue, which has a much lower propensity for type I' turn formation from a data base analysis of preferred turns. The origin of the high stability of the Asn-Gly turn is not entirely clear; data base analysis of 66 NG turns, together with molecular dynamics simulations, reveals no participation of the Asn side-chain in turn-stabilising interactions with the peptide backbone. However, hydration analysis of the molecular dynamics simulations reveals a pocket of "high density" water bridging between the Asn side-chain and peptide main-chain that suggests solvent-mediated interactions may play an important role in modulating phi,psi propensities in the NG turn region.
Nibaldo C Inestrosa - One of the best experts on this subject based on the ideXlab platform.
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the alpha helical to Beta Strand transition in the amino terminal fragment of the amyloid Beta peptide modulates amyloid formation
Journal of Biological Chemistry, 1995Co-Authors: Claudio Soto, Eduardo M Castano, Blas Frangione, Nibaldo C InestrosaAbstract:Amyloid-Beta peptide (A Beta) consists of a hydrophobic C-terminal domain (residues 29-42) that adopts Beta-Strand conformation and an N-terminal domain (amino acids 10-24) whose sequence permits the existence of a dynamic equilibrium between an alpha-helix and a Beta-Strand. In this paper we analyzed the effect of the alternate N-terminal conformations on amyloid fibril formation through the study of the analogous A Beta peptides containing single amino acidic substitutions. The single mutation of valine 18 to alanine induces a significant increment of the alpha-helical content of A Beta, determined by Fourier transform infrared spectroscopy and circular dichroism and dramatically diminishes fibrillogenesis, measured by turbidity, thioflavine T binding, Congo red staining, and electron microscopic examination. In hereditary Dutch cerebral hemorrhage with amyloidosis (a variant of Alzheimer's disease), the substitution of glutamine for glutamic acid at position 22 decreased the propensity of the A Beta N-terminal domain to adopt an alpha-helical structure, with a concomitant increase in amyloid formation. We propose that A Beta exists in an equilibrium between two species: one "able" and another "unable" to form amyloid, depending on the secondary structure adopted by the N-terminal domain. Thus, manipulation of the A Beta secondary structure with therapeutical compounds that promote the alpha-helical conformation may provides a tool to control the amyloid deposition observed in Alzheimer's disease patients.