Recent experiments suggested that ATP can effectively stabilize protein structure and inhibit protein aggregation when its concentration is less than 10 mM, which is significantly lower than cosolvent concentrations required in conventional mechanisms. The ultrahigh efficiency of ATP suggests a unique mechanism that is fundamentally different from previous models of cosolvents. In this work, we used molecular dynamics simulation and experiments to study the interactions of ATPs with three proteins: lysozyme, ubiquitin, and malate dehydrogenase. ATP tends to bind to the surface regions with high flexibility and high degree of hydration. These regions are also vulnerable to thermal perturbations. The bound ATPs further assemble into ATP clusters mediated by Mg2+ and Na+ ions. More interestingly, in Mg2+-free ATP solution, Na+ at higher concentration (150 mM under physiological conditions) can similarly mediate the formation of the ATP cluster on protein. The ATP cluster can effectively reduce the fluctuations of the vulnerable region and thus stabilize the protein against thermal perturbations. Both ATP binding and the considerable improvement of thermal stability of ATP-bound protein were verified by experiments.