Polyunsaturated Fatty Acid Modulates Membrane-Bound Monomeric α-Synuclein by Modulating Membrane Microenvironment...

There is ample evidence that both native functions and pathogenic aggregation of α-synuclein are intimately dependent on lipid interactions and fatty acid type; the regulatory mechanism however remains unclear. In the present work, using extensive atomistic molecular dynamics simulations and enhanced-sampling, we have focused on exploring the mechanism of fatty acid dependent regulation of monomeric α-Syn₁₀₀ in a native synaptic vesicle-like membrane. Our results show that α-Syn₁₀₀ spontaneously binds to the membrane through its N-terminal region (residues 1-34), where the depth of membrane insertion, the structure, and orientation of the membrane-bound α-Syn₁₀₀ and its impact on membrane structure are modulated by docosahexaenoic acid (DHA). DHA is a polyunsaturated fatty acid abundantly found in the brain and known to promote the oligomerization of α-synuclein. We found that DHA exhibits marked propensity to interact with monomeric α-Syn₁₀₀ and modulates the microenvironment of the protein by preferentially sorting DHA-containing phospholipids, depleting other phospholipids and cholesterol as well as increasing the proportion of anionic to neutral lipids in the immediate vicinity of the protein. Owing to the unique conformational flexibility, DHA chains form more lipid-packing defects in the membrane and efficiently coat the membrane-embedded surface of the protein, compared to the saturated and monounsaturated fatty acids. DHA thus makes the bilayer more amiable to protein adsorption and less prone to α-synuclein-induced perturbation associated with cytotoxicity. Indeed, in the absence of DHA, we observed significant thinning of the local bilayer membrane induced by α-Syn₁₀₀. Though α-Syn₁₀₀ is predominantly α-helical in membranes studied here, in the presence of DHA we observe formation of β-sheet/β-strands in the C-terminal region (residues 35-100) of α-Syn₁₀₀, which is extended out from the membrane surface. Notably, DHA induces β structure in the NAC domain of α-Syn₁₀₀ and promotes extended conformations as well as large solvent exposure of this hydrophobic domain, properties that are known to facilitate self-assembly of α-synuclein. To the best of our knowledge, this study for the first time provides the atomistic insights into DHA-induced regulatory mechanism of monomeric α-synuclein, having implications in protein structure and its physiological/pathological functions.