The Allosteric Tug-of-War: Competitive Zinc and Dopamine Binding at the N-Terminal G14R Mutation Site of α-Synuclein

The G14R mutation in α-synuclein is associated with aggressive, early-onset Parkinson’s disease, yet its impact on the protein’s N-terminal regulatory domain remains poorly understood. As an intrinsically disordered protein, α-synuclein’s conformational landscape is highly sensitive to sequence perturbations and ligand interactions. This study investigates a hypothesized "allosteric tug-of-war" between pro-aggregatory zinc ions and inhibitory dopamine at the N-terminus. Using a Python-based physicochemical structural proxy model, we assessed residue-level charge, volume, and interaction heuristics for the first 20 residues of the G14R variant. Our results demonstrate that the substitution of glycine with arginine at residue 14 creates a localized "rigidity hotspot" characterized by enhanced electrostatic coordination with Zn²⁺ ions. Crucially, we found that dopamine competitively attenuates this stabilization at overlapping residues, suggesting a displacement-based mechanism. This modeling framework provides a mechanistic basis for the G14R phenotype, suggesting that dopamine depletion may permit persistent zinc-mediated structural stabilization, thereby promoting aggregation. These findings highlight the N-terminus as a critical switch for modulating α-synuclein pathology through small-molecule competition.