Membrane Interactions Of Alpha-Synuclein Revealed By Multiscale Molecular Dynamics Simulations, Markov State Models, And Nmr

alpha-Synuclein (alpha S) is a presynaptic protein that binds to cell membranes and is linked to Parkinson's disease (PD). Binding of alpha S to membranes is a likely first step in the molecular pathophysiology of PD. The alpha S molecule can adopt multiple conformations, being largely disordered in water, adopting a beta-sheet conformation when present in amyloid fibrils, and forming a dynamic multiplicity of alpha-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 aS with an anionic lipid bilayer. The simulations and NMR measurements together reveal a break in the helical structure of the central non-amyloid-beta component (NAC) region of aS in the vicinity of residues 65-70, which may facilitate subsequent oligomer formation. Coarse-grained simulations of aS starting from the structure of aS 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 aS indicate incipient beta-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 alpha S via a dynamic helix break in the region of residue 65 in the NAC region. The emergent dynamic model of membrane-interacting alpha S advances our understanding of the mechanism of PD, potentially aiding the design of novel therapeutic approaches.