Cu2+, Ca2+, and methionine oxidation expose the hydrophobic α-synuclein NAC domain

Abstract α-Synuclein is an intrinsically disordered protein whose aggregation is related to Parkinson's disease and other neurodegenerative disorders. Metal cations are one of the main factors affecting the propensity of α-synuclein to aggregate, either by directly binding to it or by catalyzing the production of reactive oxygen species that oxidize it. His50, Asp121 and several additional C-terminal α-synuclein residues are binding sites for numerous metal cations, while methionine sulfoxidation occurs readily on this protein under oxidative stress conditions. Molecular dynamics simulations are an excellent tool to obtain a microscopic picture of how metal binding or methionine sulfoxidation alter the conformational preferences of α-synuclein and, hence, its aggregation propensity. In this work, we report the first coarse-grained molecular dynamics study comparing the conformational ensembles of the native protein, the protein bound to either Cu2+ or Ca2+ at its main binding sites, and the methionine-sulfoxidized protein. Our results suggest that these events alter the transient α-synuclein intramolecular contacts, inducing a greater solvent exposure of its hydrophobic, aggregation-prone NAC domain, in full agreement with a recent experimental study on Ca2+ binding. Moreover, metal-binding residues directly participate in the long-range contacts that shield this domain and regulate α-synuclein aggregation. These results provide a molecular-level rationalization of the enhanced fibrillation experimentally observed in the presence of Cu2+ or Ca2+ and the oligomerization induced by methionine sulfoxidation.