Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution

Abstract

Serine 129 can be phosphorylated in pathological inclusions formed by the intrinsically disordered protein human α-6 synuclein (AS), a key player in Parkinson’s disease and other synucleinopathies. Here, molecular simulations provide insight into the 7 structural ensemble of phosphorylated AS. The simulations allow us to suggest that phosphorylation significantly impacts the 8 structural content of the physiological AS conformational ensemble in aqueous solution, as the phosphate group is mostly solvated. 9 The hydrophobic region of AS contains β-hairpin structures, which may increase the propensity of the protein to undergo amyloid10 formation, as seen in the nonphysiological (nonacetylated) form of the protein in a recent molecular simulation study. Our findings 11 are consistent with existing experimental data with the caveat of the observed limitations of the force field for the phosphorylated 12 moiety.