ATP induces protein folding, inhibits aggregation and antagonizes destabilization by effectively mediating water-protein-ion interactions, the heart of protein folding and aggregation

Many, particularly β-dominant proteins, are prone to misfolding/aggregation in the crowded cells, a hallmark of ageing and neurodegenerative diseases including ALS. ATP provides energy to drive supramolecular machineries to control protein hemostasis in modern cells. Recently ATP was decoded to hydrotropically inhibit/dissolve liquid-liquid phase separation (LLPS) and aggregation/fibrillation at millimolar concentrations. We also found that by specific binding, ATP induces and subsequently dissolves LLPS, as well as inhibits fibrillation. Nevertheless, no report shows that ATP can directly induce protein folding. Here, by selecting two aggregation-prone ALS-causing proteins with the unfolded states, we successfully visualized the effects of ATP and 11 molecules with NMR directly on their folding and aggregation. The study reveals for the first time that ATP can induce folding at molar ratios of 2-8, the highest efficiency known so far. Intriguingly, this inducing-capacity comes from triphosphate, a key intermediate in prebiotic chemistry, which, however, also triggers aggregation. Most unexpectedly, upon joining with adenosine, the ability of triphosphate to trigger aggregation is shielded. Marvelously, ATP emerged to manifest three integrated abilities: to induce folding, inhibit aggregation and increase stability, that are absent in ATPP, AMP-PCP and AMP-PNP. Our study sheds the first light on previously-unknown roles of ATP in energy-independently controlling protein folding and aggregation by effectively mediating water-protein-ion interactions. Therefore, ATP might be not just irreplaceable for solving protein folding and aggregation problems simultaneously in primitive cells for Origin of Life, but also energy-independently operating in modern cells to regulate protein homeostasis fundamentally critical for physiology and pathology.