Abstract

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 A beta 42 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 A beta 42. In the simulations, wild type (WT) A beta 42 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 A beta 42 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 A beta 42 variants, we identify specific conformational properties of residues 23-26 that might play a key role in aggregation. Proteins 2010; 78:2600-2608. (C) 2010 Wiley-Liss, Inc.

Keywords

amyloid-beta; mutations; all atom; implicit solvent; Monte Carlo; J-coupling constants; chemical shifts

Published in

Proteins
2010, volume: 78, number: 12, pages: 2600-2608
Publisher: WILEY-LISS

Authors' information