Curvature Dynamics of α-Synuclein Familial Parkinson's Disease Mutants: Molecular Dynamics Simulations of the Micelle- and Membrane-Bound Forms

Abstract

α-synuclein remains a protein of interest due to its propensity to form fibrillar aggregates in neurodegenerative disease and its putative function in synaptic vesicle regulation. We have performed a series of all-atom molecular dynamics simulations of wild-type α-synuclein and the three Parkinson's disease familial mutants, A30P, A53T, and E46K, bound to an SDS detergent micelle. Our analysis explains how α-synuclein adapts to, and alters, highly curved membrane surfaces through helical bending. We find that α-synuclein binding induces significant deformation in the micelle, flattening the structure and decreasing its surface area. Similar effects on biological membranes would relieve curvature stress, ameliorating the propensity to fuse, and would perhaps explain α-synuclein's role in stabilizing synaptic vesicles. Consistent with the experimentally determined behavior of A30P, the proline dramatically destabilizes the secondary structure, inducing reversible unfolding up- and down-stream of the substitution. The E46K mutation provides an additional electrostatic interaction between the protein and micelle, offering an explanation for the mutants increased affinity. In the case of the A53T mutant, recent NMR data suggested that an enthalpic interaction might be responsible for a slight rigidification of the helical structure. We show that the equilibrium structure of A53T contains a very tight hydrogen-bond between the threonine's hydroxyl and the backbone carbonyl of Val49. We speculate as to the potential effects of these dynamic and structural changes, on α-synuclein's role in neural signaling. In order to assess the applicability of these results to biological membranes, we have performed simulations of the wild-type and mutants on a DOPS bilayer. These simulations reproduce the major conclusions of the micelle-bound simulations, suggesting that the detergent micelle is an adequate model system.