To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-β protein into β-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC (70% POPC, and 30% cholesterol) and physiologically relevant concentrations of sphingomyelin (SM) (30% SM, 40% POPC, and 30% cholesterol), and the GM1 ganglioside (5% GM1, 70% POPC, and 25% cholesterol). The increased bilayer rigidity provided by SM (and to a lesser degree, GM1) reduced the interactions between the SM-enriched bilayer and the N-terminus of Aβ42 (and also residues Ser26, Asn27, and Lys28), which facilitated the formation of a β-sheet in the normally disordered N-terminal region. Aβ42 remained anchored to the SM-enriched bilayer through hydrogen bonds with the side chain of Arg5. With β-sheets in the at the N and C termini, the structure of Aβ42 in the sphingomyelin-enriched bilayer most resembles β-sheet-rich structures found in higher-ordered Aβ fibrils. Conversely, when bound to a bilayer comprised of 5% GM1, the conformation remained similar to that observed in the absence of GM1, with Aβ42 only making contact with one or two GM1 molecules. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

Department of Physics University of Helsinki P O Box 64 FI 00014 Helsinki Finland; Department of Physics Tampere University of Technology P O Box 692 FI 33101 Tampere Finland

Institute of Complex Systems Structural Biochemistry Forschungszentrum Jülich 52425 Jülich Germany; CEITEC Central European Institute of Technology Masaryk University Kamenice 753 5 Brno 625 00 Czech Republic

Institute of Complex Systems Structural Biochemistry Forschungszentrum Jülich 52425 Jülich Germany; Institute of Theoretical and Computational Chemistry Heinrich Heine University Düsseldorf Universitätsstrasse 1 40225 Düsseldorf Germany

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