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Protein Science (2007), 16:1214-1222. Published by Cold Spring Harbor Laboratory Press. Copyright © 2007 The Protein Society
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Similarities in the thermodynamics and kinetics of aggregation of disease-related Abeta(1–40) peptides

Jessica Meinhardt1, Gian Gaetano Tartaglia2, Amol Pawar2, Tony Christopeit1, Peter Hortschansky3, Volker Schroeckh3, Christopher M. Dobson2, Michele Vendruscolo2, and Marcus Fändrich1

1 Leibniz-Institut für Altersforschung, Fritz-Lipmann-Institut, D-07745 Jena, Germany
2 Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom
3 Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie, Hans-Knöll-Institut, D-07745 Jena, Germany

(RECEIVED December 18, 2006; FINAL REVISION February 27, 2007; ACCEPTED March 7, 2007)

Increasing evidence indicates that polypeptide aggregation often involves a nucleation and a growth phase, although the relationship between the factors that determine these two phases has not yet been fully clarified. We present here an analysis of several mutations at different sites of the Abeta(1–40) peptide, including those associated with early onset forms of the Alzheimer's disease, which reveals that the effects of specific amino acid substitutions in the sequence of this peptide are strongly modulated by their structural context. Nevertheless, mutations at different positions perturb in a correlated manner the free energies of aggregation as well as the lag times and growth rates. We show that these observations can be rationalized in terms of the intrinsic propensities for aggregation of the Abeta(1–40) sequence, thus suggesting that, in the case of this peptide, the determinants of the thermodynamics and of the nucleation and growth of the aggregates have a similar physicochemical basis.

Keywords: conformational disease; kinetics; neurodegeneration; protein folding; Alzheimer's disease


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