Fig. 1. Hypothetical models of αS–ATP interactions. (a) Upper panel: WT αS amino acid sequence, containing nine pseudo-apolipoprotein-like repeats (underlined), acidic (bolded) and basic (italicized) residues.¹⁷ The N-terminus, NAC region and C-terminus are colored in blue, yellow and red, respectively.¹⁶ Lower panel: general αS aggregation mechanism involving disruption of the long-range N- to C-terminal monomer contacts, leading to opening and subsequent aggregation of αS into oligomers and fibrils.^21–24 (b) One hypothetical model of the ATP–αS interaction based upon the interaction of ATP with proteins in the crystalline lens, whereby the adenine group of ATP clusters over protein hydrophobic patches and the triphosphate electrostatically repels other bound monomers to inhibit aggregation.²⁵ (c) Another viable model for ATP–αS interactions, suggesting that ATP could bridge αS monomers and enhance aggregation via the phosphate-mediated targeting of lysine residues (designated by “+” symbols) in the αS N-terminus, as is the case for tau protein.⁶ (d) Model for Mg²⁺-mediated ATP–αS interaction proposed by Nishizawa et al., whereby Mg²⁺ ions interact with the αS C-terminus and “bridge” indirect, non-specific interactions between the protein and ATP.¹².