Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster

Francesco Attanasio, Marino Convertino, Andrea Magno, Amedeo Caflisch, Alessandra Corazza, Haritha Haridas, Gennaro Esposito, Sebastiano Cataldo, Bruno Pignataro, Danilo Milardi, Enrico Rizzarelli

Research output: Contribution to journalArticle

Abstract

Aggregation of the amyloid-β peptide (Aβ) into fibrillar structures is a hallmark of Alzheimer's disease. Thus, preventing self-assembly of the Aβ peptide is an attractive therapeutic strategy. Here, we used experimental techniques and atomistic simulations to investigate the influence of carnosine, a dipeptide naturally occurring in the brain, on Aβ aggregation. Scanning force microscopy, circular dichroism and thioflavin T fluorescence experiments showed that carnosine does not modify the conformational features of Aβ42 but nonetheless inhibits amyloid growth. Molecular dynamics (MD) simulations indicated that carnosine interacts transiently with monomeric Aβ42 by salt bridges with charged side chains, and van der Waals contacts with residues in and around the central hydrophobic cluster (17LVFFA21). NMR experiments on the nonaggregative fragment Aβ12-28 did not evidence specific intermolecular interactions between the peptide and carnosine, in agreement with MD simulations. However, a close inspection of the spectra revealed that carnosine interferes with the local propensity of the peptide to form backbone hydrogen bonds close to the central hydrophobic cluster (residues E22, S26 and N27). Finally, MD simulations of aggregation-prone Aβ heptapeptide segments show that carnosine reduces the propensity to form intermolecular backbone hydrogen bonds in the region 18-24. Taken together, the experimental and simulation results (cumulative MD sampling of 0.2 ms) suggest that, despite the inability of carnosine to form stable contacts with Aβ, it might block the pathway toward toxic aggregates by perturbing the hydrogen bond network near residues with key roles in fibrillogenesis. Dropping your H's/Ban the bond: Inspired by the body of evidence for a neuroprotective activity of carnosine, we investigated whether this dipeptide hinders Aβ42 growth in vitro. Our results indicate that despite the inability of carnosine to form stable contacts with Aβ, it might block aggregation by perturbing the propensity of the peptide to form H-bonds.

Original languageEnglish (US)
Pages (from-to)583-592
Number of pages10
JournalChemBioChem
Volume14
Issue number5
DOIs
StatePublished - Mar 1 2013

Fingerprint

Carnosine
Agglomeration
Molecular Dynamics Simulation
Molecular dynamics
Hydrogen
Hydrogen bonds
Peptides
Dipeptides
Amyloid
Computer simulation
compound A 12
Atomic Force Microscopy
Poisons
Growth
Circular Dichroism
Self assembly
Atomic force microscopy
Brain
Alzheimer Disease
Salts

Keywords

  • Alzheimer's disease
  • Carnosine
  • Molecular dynamics
  • Neuroprotective agent
  • Nutraceutical compounds
  • Protein-protein interactions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Organic Chemistry

Cite this

Attanasio, F., Convertino, M., Magno, A., Caflisch, A., Corazza, A., Haridas, H., ... Rizzarelli, E. (2013). Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster. ChemBioChem, 14(5), 583-592. https://doi.org/10.1002/cbic.201200704

Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster. / Attanasio, Francesco; Convertino, Marino; Magno, Andrea; Caflisch, Amedeo; Corazza, Alessandra; Haridas, Haritha; Esposito, Gennaro; Cataldo, Sebastiano; Pignataro, Bruno; Milardi, Danilo; Rizzarelli, Enrico.

In: ChemBioChem, Vol. 14, No. 5, 01.03.2013, p. 583-592.

Research output: Contribution to journalArticle

Attanasio, F, Convertino, M, Magno, A, Caflisch, A, Corazza, A, Haridas, H, Esposito, G, Cataldo, S, Pignataro, B, Milardi, D & Rizzarelli, E 2013, 'Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster', ChemBioChem, vol. 14, no. 5, pp. 583-592. https://doi.org/10.1002/cbic.201200704
Attanasio, Francesco ; Convertino, Marino ; Magno, Andrea ; Caflisch, Amedeo ; Corazza, Alessandra ; Haridas, Haritha ; Esposito, Gennaro ; Cataldo, Sebastiano ; Pignataro, Bruno ; Milardi, Danilo ; Rizzarelli, Enrico. / Carnosine Inhibits Aβ42 Aggregation by Perturbing the H-Bond Network in and around the Central Hydrophobic Cluster. In: ChemBioChem. 2013 ; Vol. 14, No. 5. pp. 583-592.
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AU - Haridas, Haritha

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