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Moiety-specific mechanism of ATP's hydrotropic action on α-synuclein
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DOI：10.1039/D6CP00884D.png)
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Abstract
En 中文
Adenosine triphosphate (ATP); the universal energy currency of life; also acts as a biological hydrotrope that maintains protein solubility. However; the molecular mechanism underlying its hydrotropic action; particularly how its distinct chemical moieties contribute to modulating protein conformation and preventing aggregation; remains unclear. Here; we combined NMR spectroscopy and molecular dynamics (MD) simulations to dissect the moiety-specific interactions between ATP and α-synuclein; an intrinsically disordered protein implicated in Parkinson's disease. NMR titration experiments monitoring ATP signals revealed that the adenine ring of ATP formed weak multisite interactions with α-synuclein; whereas the triphosphate group formed fewer but stronger contacts. MD simulations showed that the triphosphate-mediated contacts occurred primarily at N-terminal lysine residues and disrupted long-range intramolecular contacts; resulting in conformational expansion of α-synuclein. Energetic analysis indicated that this expansion incurred a conformational energy cost that was balanced by more favorable solvation. Based on these findings; we propose a “hierarchical binding hydrotrope mechanism”; in which the predominant contribution of each ATP moiety shifts with ATP concentration because the two moieties differ in microscopic affinity and the number of accessible interaction sites. Triphosphate-mediated binding; limited by the number of available binding sites; increases preferentially at lower ATP concentrations; whereas adenine-mediated binding increases progressively at higher concentrations. This mechanism provides a molecular basis for the concentration-dependent hydrotropic effects of ATP and clarifies how this metabolite modulates the conformational properties of aggregation-prone proteins under physiological conditions.
Keywords:
ATP
hydrotrope
α-synuclein
molecular dynamics
NMR spectroscopy
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