Membrane Interactions of α-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR

Sarah Beth T.A. Amos, Thomas C. Schwarz, Jiye Shi, Benjamin P. Cossins, Terry S. Baker, Richard J. Taylor, Robert Konrat, Mark S.P. Sansom (Corresponding author)

Publications: Contribution to journalArticlePeer Reviewed

Abstract

α-Synuclein (αS) is a presynaptic protein that binds to cell membranes and is linked to Parkinson’s disease (PD). Binding of αS to membranes is a likely first step in the molecular pathophysiology of PD. The αS molecule can adopt multiple conformations, being largely disordered in water, adopting a β-sheet conformation when present in amyloid fibrils, and forming a dynamic multiplicity of α-helical conformations when bound to lipid bilayers and related membrane-mimetic surfaces. Multiscale molecular dynamics simulations in conjunction with nuclear magnetic resonance (NMR) and cross-linking mass spectrometry (XLMS) measurements are used to explore the interactions of αS with an anionic lipid bilayer. The simulations and NMR measurements together reveal a break in the helical structure of the central non-amyloid-β component (NAC) region of αS in the vicinity of residues 65–70, which may facilitate subsequent oligomer formation. Coarse-grained simulations of αS starting from the structure of αS when bound to a detergent micelle reveal the overall pattern of protein contacts to anionic lipid bilayers, while subsequent all-atom simulations provide details of conformational changes upon membrane binding. In particular, simulations and NMR data for liposome-bound αS indicate incipient β-strand formation in the NAC region, which is supported by intramolecular contacts seen via XLMS and simulations. Markov state models based on the all-atom simulations suggest a mechanism of conformational change of membrane-bound αS via a dynamic helix break in the region of residue 65 in the NAC region. The emergent dynamic model of membrane-interacting αS advances our understanding of the mechanism of PD, potentially aiding the design of novel therapeutic approaches.
Original languageEnglish
Pages (from-to)2929-2941
Number of pages13
JournalJournal of Physical Chemistry B
Volume125
Issue number11
DOIs
Publication statusPublished - 15 Mar 2021

Austrian Fields of Science 2012

  • 104017 Physical chemistry
  • 104022 Theoretical chemistry
  • 106041 Structural biology

Keywords

  • BROKEN HELIX
  • FORCE-FIELD
  • IN-VIVO
  • BINDING
  • INSIGHTS
  • DISEASE
  • OLIGOMERS
  • PEPTIDES
  • VESICLE
  • CURVATURE

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