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

Rajendra Nath Dasari^1*

Abstract

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.

Keywords

α-Synuclein, G14R Mutation, Zinc Coordination, Dopamine Competition, Intrinsically Disordered Proteins (IDPs)

Corresponding Author

Rajendra Nath Dasari, Independent Researcher, Wake Early College of Health and Sciences, USA.

Citation

Dasari, R. N. (2026). The Allosteric Tug-of-War: Competitive Zinc and Dopamine Binding at the N-Terminal G14R Mutation Site of α-Synuclein. Med Pharmacol Open Access. 1(1), 01-11.