Effects of Ligands on Unfolding of the Amyloid β-Peptide Central Helix: Mechanistic Insights from Molecular Dynamics Simulations

Mika Ito,Jan Johansson,Lennart Nilsson,Roger Strömberg,Franca Fraternali

doi:10.1371/journal.pone.0030510

Abstract

Polymerization of the amyloid β-peptide (Aβ), a process which requires that the helical structure of Aβ unfolds beforehand, is suspected to cause neurodegeneration in Alzheimer's disease. According to recent experimental studies, stabilization of the Aβ central helix counteracts Aβ polymerization into toxic assemblies. The effects of two ligands (Dec-DETA and Pep1b), which were designed to bind to and stabilize the Aβ central helix, on unfolding of the Aβ central helix were investigated by molecular dynamics simulations. It was quantitatively demonstrated that the stability of the Aβ central helix is increased by both ligands, and more effectively by Pep1b than by Dec-DETA. In addition, it was shown that Dec-DETA forms parallel conformations with β-strand-like Aβ, whereas Pep1b does not and instead tends to bend unwound Aβ. The molecular dynamics results correlate well with previous experiments for these ligands, which suggest that the simulation method should be useful in predicting the effectiveness of novel ligands in stabilizing the Aβ central helix. Detailed Aβ structural changes upon loss of helicity in the presence of the ligands are also revealed, which gives further insight into which ligand may lead to which path subsequent to unwinding of the Aβ central helix.

Highlights

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in aging people
Effects of the Ligands on Stability of the amyloid b-peptide (Ab) Central Helix To examine whether the Ab central helix eventually unfolded by the end of the simulation, the average backbone rootmean-square deviation (RMSD) of the Ab middle region (15–24) and the average number of a-helical O(i)-HN(i+4) backbone hydrogen bonds (aHBs) of the Ab middle region calculated for the last 2 ns of the each 20 ns simulation, where fluctuation of the Ab backbone RMSD is relatively small in every trajectory, were analyzed (Table 1)
It was ascertained that the Ab central helix maintained its helical conformation during the whole simulations or refolded after partial unfolding by the end of the simulations in the group A trajectories, that it partially unfolded by the end of the simulations in the group B trajectories, and that it completely unfolded by the end of the simulations in the group C trajectories

Summary

Introduction

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders in aging people. Nuclear magnetic resonance (NMR) data showed that Ab(1–40) adopts a folded structure including two a-helical regions (residues 15–24 and 29– 35) in water/sodium dodecyl sulfate (SDS) micelles which provide a water-membrane interface mimicking environment [4,5], and that Ab(1–42) adopts an unfolded structure including two bstrands (residues 17–21 and 31–36) in aqueous solution [6]. Using NMR it has been shown that an Ab(1–42) fibril is a b-sheet composed of two b-strands (residues 18–26 and 31–42) [7]. These structural data indicate that, once Ab departs from the membrane to the extracellular fluid, its a-helical regions unfold to elongated or b-strand-like forms, and that the b-strands of Ab enable formation of b-sheets of fibrils and prefibrillar aggregates

Methods

Results

Conclusion