Computational design and evaluation of β‐sheet breaker peptides for destabilizing Alzheimer's amyloid‐β 42 protofibrils

2019 ◽  
Vol 120 (10) ◽  
pp. 17935-17950 ◽  
Author(s):  
Suniba Shuaib ◽  
Simranjeet Singh Narang ◽  
Deepti Goyal ◽  
Bhupesh Goyal
Keyword(s):  
Amyloid Β ◽  
Computational Design ◽  
Β Sheet

scholarly journals Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa

2021 ◽  
Vol 22 (3) ◽  
pp. 1225
Author(s):  
Ziao Fu ◽  
William E. Van Nostrand ◽  
Steven O. Smith
Keyword(s):  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Aβ Oligomers ◽  
Dominant Component ◽  
Fibril Structure ◽  
Predominant Component ◽  
Aβ Aggregation ◽  
Aβ Fibrils ◽  
Soluble Aβ Oligomers ◽  
Β Sheet

The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.

scholarly journals Assessment of Amyloid Forming Tendency of Peptide Sequences from Amyloid Beta and Tau Proteins Using Force-Field, Semi-Empirical, and Density Functional Theory Calculations

2021 ◽  
Vol 22 (6) ◽  
pp. 3244
Author(s):  
Charuvaka Muvva ◽  
Natarajan Arul Murugan ◽  
Venkatesan Subramanian
Keyword(s):  
Force Field ◽  
Density Functional ◽  
Amyloid Β ◽  
Density Functional Theory Calculations ◽  
Tau Proteins ◽  
Functional Theory ◽  
Energy Profiles ◽  
Α Helix ◽  
Semi Empirical ◽  
Β Sheet

A wide variety of neurodegenerative diseases are characterized by the accumulation of protein aggregates in intraneuronal or extraneuronal brain regions. In Alzheimer’s disease (AD), the extracellular aggregates originate from amyloid-β proteins, while the intracellular aggregates are formed from microtubule-binding tau proteins. The amyloid forming peptide sequences in the amyloid-β peptides and tau proteins are responsible for aggregate formation. Experimental studies have until the date reported many of such amyloid forming peptide sequences in different proteins, however, there is still limited molecular level understanding about their tendency to form aggregates. In this study, we employed umbrella sampling simulations and subsequent electronic structure theory calculations in order to estimate the energy profiles for interconversion of the helix to β-sheet like secondary structures of sequences from amyloid-β protein (KLVFFA) and tau protein (QVEVKSEKLD and VQIVYKPVD). The study also included a poly-alanine sequence as a reference system. The calculated force-field based free energy profiles predicted a flat minimum for monomers of sequences from amyloid and tau proteins corresponding to an α-helix like secondary structure. For the parallel and anti-parallel dimer of KLVFFA, double well potentials were obtained with the minima corresponding to α-helix and β-sheet like secondary structures. A similar double well-like potential has been found for dimeric forms for the sequences from tau fibril. Complementary semi-empirical and density functional theory calculations displayed similar trends, validating the force-field based free energy profiles obtained for these systems.

scholarly journals Amyloid–β-Sheet Formation at the Air-Water Interface

1999 ◽  
Vol 77 (6) ◽  
pp. 3305-3310 ◽  
Author(s):  
Claudia Schladitz ◽  
Euridice P. Vieira ◽  
Horst Hermel ◽  
Helmuth Möhwald
Keyword(s):  
Amyloid Β ◽  
Water Interface ◽  
Air Water Interface ◽  
Β Sheet

scholarly journals Physiologically-relevant levels of sphingomyelin, but not GM1, induces a β-sheet-rich structure in the amyloid-β(1-42) monomer

2018 ◽  
Vol 1860 (9) ◽  
pp. 1709-1720 ◽  
Author(s):  
Michael C. Owen ◽  
Waldemar Kulig ◽  
Chetan Poojari ◽  
Tomasz Rog ◽  
Birgit Strodel
Keyword(s):  
Amyloid Β ◽  
Β Sheet

Dissociation of β-Sheet Stacking of Amyloid β Fibrils by Irradiation of Intense, Short-Pulsed Mid-infrared Laser

2018 ◽  
Vol 38 (5) ◽  
pp. 1039-1049 ◽  
Author(s):  
Takayasu Kawasaki ◽  
Toyonari Yaji ◽  
Toshiaki Ohta ◽  
Koichi Tsukiyama ◽  
Kazuhiro Nakamura
Keyword(s):  
Amyloid Β ◽  
Infrared Laser ◽  
Mid Infrared ◽  
Β Sheet

scholarly journals Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2316 ◽  
Author(s):  
Qiuchen Zheng ◽  
Micheal T. Kebede ◽  
Merc M. Kemeh ◽  
Saadman Islam ◽  
Bethany Lee ◽  
...  
Keyword(s):  
Self Assembly ◽  
Complex Disease ◽  
Red Wine ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Therapeutic Agents ◽  
Mechanistic Studies ◽  
Naturally Occurring ◽  
Aβ Oligomerization ◽  
Β Sheet

The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer’s disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau. Polyphenols modulate the enzymatic processing of the amyloid-β precursor protein and inhibit toxic Aβ oligomerization by enhancing the clearance of Aβ42 monomer, modulating monomer–monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau β-sheet formation. The anti-Aβ-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms.

scholarly journals Rippled β-Sheet Formation by an Amyloid-β Fragment Indicates Expanded Scope of Sequence Space for Enantiomeric β-Sheet Peptide Coassembly

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1983 ◽  
Author(s):  
Jennifer M. Urban ◽  
Janson Ho ◽  
Gavin Piester ◽  
Riqiang Fu ◽  
Bradley L. Nilsson
Keyword(s):  
Sequence Space ◽  
Self Assembly ◽  
Solid State Nmr ◽  
Amyloid Β ◽  
Amino Acid Residues ◽  
Hydrophobic Amino Acid ◽  
Amphipathic Peptide ◽  
Sequence Patterns ◽  
Β Sheets ◽  
Β Sheet

In 1953, Pauling and Corey predicted that enantiomeric β-sheet peptides would coassemble into so-called “rippled” β-sheets, in which the β-sheets would consist of alternating l- and d-peptides. To date, this phenomenon has been investigated primarily with amphipathic peptide sequences composed of alternating hydrophilic and hydrophobic amino acid residues. Here, we show that enantiomers of a fragment of the amyloid-β (Aβ) peptide that does not follow this sequence pattern, amyloid-β (16–22), readily coassembles into rippled β-sheets. Equimolar mixtures of enantiomeric amyloid-β (16–22) peptides assemble into supramolecular structures that exhibit distinct morphologies from those observed by self-assembly of the single enantiomer pleated β-sheet fibrils. Formation of rippled β-sheets composed of alternating l- and d-amyloid-β (16–22) is confirmed by isotope-edited infrared spectroscopy and solid-state NMR spectroscopy. Sedimentation analysis reveals that rippled β-sheet formation by l- and d-amyloid-β (16–22) is energetically favorable relative to self-assembly into corresponding pleated β-sheets. This work illustrates that coassembly of enantiomeric β-sheet peptides into rippled β-sheets is not limited to peptides with alternating hydrophobic/hydrophilic sequence patterns, but that a broader range of sequence space is available for the design and preparation of rippled β-sheet materials.

Copper selectively triggers β-sheet assembly of an N-terminally truncated amyloid β-peptide beginning with Glu3

2004 ◽  
Vol 98 (1) ◽  
pp. 10-14 ◽  
Author(s):  
Takashi Miura ◽  
Sayoko Mitani ◽  
Chiho Takanashi ◽  
Nobuhiro Mochizuki
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Β Sheet

scholarly journals Systemic Catabolism of Alzheimer's Aβ40 and Aβ42

2004 ◽  
Vol 279 (44) ◽  
pp. 45897-45908 ◽  
Author(s):  
Jorge Ghiso ◽  
Marcos Shayo ◽  
Miguel Calero ◽  
Douglas Ng ◽  
Yasushi Tomidokoro ◽  
...  
Keyword(s):  
Competitive Inhibition ◽  
Amyloid Β ◽  
Cell Trapping ◽  
Radiolabeled Peptides ◽  
Organ Uptake ◽  
Major Organ ◽  
Disease Stages ◽  
Peptide Uptake ◽  
Β Sheet

To better understand the physiologic excretion and/or catabolism of circulating peripheral amyloid β (Aβ), we labeled human Aβ40 (monomeric, with predominant unordered structure) and Aβ42 (mixture of monomers and oligomers in ∼50:50 ratio, rich in β-sheet conformation) with either Na125I or125I-tyramine cellobiose, also known as the cell-trapping ligand procedure, testing their blood clearance and organ uptake in B6SJLF1/J mice. Irrespective of the labeling protocol, the peptide conformation, and the degree of oligomerization, both Aβ40 and Aβ42 showed a short half-life of 2.5–3.0 min. The liver was the major organ responsible for plasma clearance, accounting for >60% of the peptide uptake, followed by the kidney.In vivo, hepatocytes captured >90% of the radiolabeled peptides which, after endocytosis, were preferentially catabolized and excreted into the bile. Biliary excretion of intact as well as partially degraded Aβ species became obviously relevant at doses above 10 μg. The use of biotin-labeled Aβ allowed the visualization of the interaction with HepG2 cells in culture, whereas competitive inhibition experiments with unlabeled Aβ demonstrated the specificity of the binding. The capability of the liver to uptake, catabolize, and excrete large doses of Aβ, several orders of magnitude above its physiologic concentration, may explain not only the femtomolar plasma levels of Aβ but the little fluctuation observed with age and disease stages.

scholarly journals Boosting protein stability with the computational design of β-sheet surfaces

2016 ◽  
Vol 25 (3) ◽  
pp. 702-710 ◽  
Author(s):  
Doo Nam Kim ◽  
Timothy M. Jacobs ◽  
Brian Kuhlman
Keyword(s):  
Protein Stability ◽  
Computational Design ◽  
Β Sheet
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