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Carnosine Inhibits Aβ 42 Aggregation by Perturbing the H‐Bond Network in and around the Central Hydrophobic Cluster
Author(s) -
Attanasio Francesco,
Convertino Marino,
Magno Andrea,
Caflisch Amedeo,
Corazza Alessandra,
Haridas Haritha,
Esposito Gennaro,
Cataldo Sebastiano,
Pignataro Bruno,
Milardi Danilo,
Rizzarelli Enrico
Publication year - 2013
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201200704
Subject(s) - chemistry , carnosine , hydrogen bond , molecular dynamics , peptide , hydrophobic effect , dipeptide , intermolecular force , stereochemistry , circular dichroism , biophysics , crystallography , protein aggregation , van der waals force , molecule , computational chemistry , biochemistry , organic chemistry , biology
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 ( 17 LVFFA 21 ). 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.