Physiologically-relevant levels of sphingomyelin, but not GM1, induces a β-sheet-rich structure in the amyloid-β(1-42) monomer

Michael C Owen; Waldemar Kulig; Chetan Poojari; Tomasz Rog; Birgit Strodel

doi:10.1016/j.bbamem.2018.03.026

Physiologically-relevant levels of sphingomyelin, but not GM1, induces a β-sheet-rich structure in the amyloid-β(1-42) monomer

Biochim Biophys Acta Biomembr. 2018 Sep;1860(9):1709-1720. doi: 10.1016/j.bbamem.2018.03.026. Epub 2018 Apr 4.

Authors

Michael C Owen¹, Waldemar Kulig², Chetan Poojari², Tomasz Rog², Birgit Strodel³

Affiliations

¹ Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany; CEITEC - Central European Institute of Technology, Masaryk University, Kamenice 753/5, Brno 625 00, Czech Republic. Electronic address: michael.owen@ceitec.muni.cz.
² 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.
³ Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany; Institute of Theoretical and Computational Chemistry, Heinrich Heine University Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany. Electronic address: b.strodel@fz-juelich.de.

PMID: 29626441
DOI: 10.1016/j.bbamem.2018.03.026

Abstract

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.

Keywords: Amyloid-β peptide; GM1; Gangliosides; Lipid rafts; Membrane simulations; Molecular dynamics; Peptide-ganglioside interactions; Peptide-membrane interactions; Sphingomyelin.