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Proteins. 2010 Sep;78(12):2600-8. doi: 10.1002/prot.22775.

Comparing the folding free-energy landscapes of Abeta42 variants with different aggregation properties.

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Computational Biology and Biological Physics, Lund University, Sölvegatan 14A, SE-223 62 Lund, Sweden.


The properties of the amyloid-beta peptide that lead to aggregation associated with Alzheimer's disease are not fully understood. This study aims at identifying conformational differences among four variants of full-length Abeta42 that are known to display very different aggregation properties. By extensive all-atom Monte Carlo simulations, we find that a variety of beta-sheet structures with distinct turns are readily accessible for full-length Abeta42. In the simulations, wild type (WT) Abeta42 preferentially populates two major classes of conformations, either extended with high beta-sheet content or more compact with lower beta-sheet content. The three mutations studied alter the balance between these classes. Strong mutational effects are observed in a region centered at residues 23-26, where WT Abeta42 tends to form a turn. The aggregation-accelerating E22G mutation associated with early onset of Alzheimer's disease makes this turn region conformationally more diverse, whereas the aggregation-decelerating F20E mutation has the reverse effect, and the E22G/I31E mutation reduces the turn population. Comparing results for the four Abeta42 variants, we identify specific conformational properties of residues 23-26 that might play a key role in aggregation.

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