Plasticity of Membrane Binding by the Central Region of alpha-Synuclein

Membrane binding by alpha-synuclein (alpha S), an intrinsically disordered protein whose aggregation is associated with Parkinson's disease, is a key step in determining its biological properties under both physiological and pathological conditions. Upon membrane interaction, alpha S retains a partial level of structural disorder despite acquiring alpha-helical content. In the membrane-bound state, the equilibrium between the helical-bound and disordered-detached states of the central region of alpha S (residues 65-97) has been involved in a double-anchor mechanism that promotes the clustering of synaptic vesicles. Herein, we investigated the underlying molecular bases of this equilibrium using enhanced coarse-grained molecular dynamics simulations. The results enabled clarifying the conformational dependencies of the membrane affinity by this protein region that, in addition to playing a role in physiological membrane binding, has key relevance for the aggregation of alpha S and the mechanisms of the toxicity of the resulting assemblies.