posted on 2021-03-15, 14:18authored bySarah-Beth
T. A. Amos, Thomas C. Schwarz, Jiye Shi, Benjamin P. Cossins, Terry S. Baker, Richard J. Taylor, Robert Konrat, Mark S. P. Sansom
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.