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Abstract

Alzheimer's disease (AD) pathogenesis is associated with formation of amyloid fibrils caused by polymerization of the amyloid beta-peptide (A beta), which is a process that requires unfolding of the native helical structure of A beta. According to recent experimental studies, stabilization of the A beta central helix is effective in preventing A beta polymerization into toxic assemblies. To uncover the fundamental mechanism of unfolding of the A beta central helix, we performed molecular dynamics simulations for wild-type (WT), V18A/F19A/F20A mutant (MA), and V18L/F19L/F20L mutant (ML) models of the A beta central helix. It was quantitatively demonstrated that the stability of the alpha-helical conformation of both MA and ML is higher than that of WT, indicating that the alpha-helical propensity of the three nonpolar residues (18, 19, and 20) is the main factor for the stability of the whole A beta central helix and that their hydrophobicity plays a secondary role. WT was found to completely unfold by a three-step mechanism: 1) loss of alpha-helical backbone hydrogen bonds, 2) strong interactions between nonpolar sidechains, and 3) strong interactions between polar sidechains. WT did not completely unfold in cases when any of the three steps was omitted. MA and ML did not completely unfold mainly due to the lack of the first step. This suggests that disturbances in any of the three steps would be effective in inhibiting the unfolding of the A beta central helix. Our findings would pave the way for design of new drugs to prevent or retard AD.

Published in

PLoS ONE
2011, volume: 6, number: 3, article number: e17587
Publisher: PUBLIC LIBRARY SCIENCE

SLU Authors

UKÄ Subject classification

Other Clinical Medicine

Publication identifier

  • DOI: https://doi.org/10.1371/journal.pone.0017587

Permanent link to this page (URI)

https://res.slu.se/id/publ/68294