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Peptides. 2010 Nov;31(11):2100-8. doi: 10.1016/j.peptides.2010.07.015. Epub 2010 Aug 4.

Molecular dynamics simulations of Aβ fibril interactions with β-sheet breaker peptides.

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  • 1School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. r.a.bryce@manchester.ac.uk


Accumulation and aggregation of the 42-residue amyloid-β (Aβ) protein fragment, which originates from the cleavage of amyloid precursor protein by β and γ secretase, correlates with the pathology of Alzheimer's disease (AD). Possible therapies for AD include peptides based on the Aβ sequence, and recently identified small molecular weight compounds designed to mimic these, that interfere with the aggregation of Aβ and prevent its toxic effects on neuronal cells in culture. Here, we use molecular dynamics simulations to compare the mode of interaction of an active (LPFFD) and inactive (LHFFD) β-sheet breaker peptide with an Aβ fibril structure from solid-state NMR studies. We found that LHFFD had a weaker interaction with the fibril than the active peptide, LPFFD, from geometric and energetic considerations, as estimated by the MM/PBSA approach. Cluster analysis and computational alanine scanning identified important ligand-fibril contacts, including a possible difference in the effect of histidine on ligand-fibril π-stacking interactions, and the role of the proline residue in establishing contacts that compete with those essential for maintenance of the inter-monomer β-sheet structure of the fibril. Our results show that molecular dynamics simulations can be a useful way to classify the stability of docking sites. These mechanistic insights into the ability of LPFFD to reverse aggregation of toxic Aβ will guide the redesign of lead compounds, and aid in developing realistic therapies for AD and other diseases of protein aggregation.

Copyright © 2010 Elsevier Inc. All rights reserved.

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