Adenosine triphosphate as a modulator of protein interactions and stability

Beyond its classical role as the cellular energy currency, adenosine triphosphate (ATP) can directly modulate protein stability, solubility and self-assembly through weak nonspecific interactions. Here, we summarise the current experimental and theoretical understanding of noncanonical ATP-protein interactions and their implications for folding, aggregation and phase stability. Recent studies show that ATP interacts primarily with positively charged residues such as lysine (Lys) and arginine (Arg) via electrostatic and hydrogen-bonding interactions, with additional cation-π or π-π contacts in some systems. These interactions modulate protein folding, conformational stability and aggregation by shifting the balance between folded and unfolded states. For intrinsically disordered and amyloidogenic proteins, ATP acts as a concentration-dependent regulator that can promote, suppress or remodel phase-separated condensates and fibrillar assemblies depending on protein sequence, ATP concentration and solution conditions. In natively folded proteins, ATP influences protein-protein interactions and phase behaviour, often enhancing colloidal stability and suppressing aggregation. Complexation with Mg²⁺ further modulates these effects by altering phosphate charge accessibility and, in some systems, changing the balance between binding, bridging and solubilisation. Together, these observations establish ATP as a multivalent small-molecule modulator of protein behaviour.