Abstract
Recent studies reported that adenosine triphosphate (ATP) could inhibit and enhance the phase separation in prion-like proteins. The molecular mechanism underlying such a puzzling phenomenon remains elusive. Here, taking the fused in sarcoma (FUS) solution as an example, we comprehensively reveal the underlying mechanism by which ATP regulates phase separation by combining the semiempirical quantum mechanical method, mean-field theory, and molecular simulation. At the microscopic level, ATP acts as a bivalent or trivalent binder; at the macroscopic level, the reentrant phase separation occurs in dilute FUS solutions, resulting from the ATP concentration-dependent binding ability under different conditions. The ATP concentration for dissolving the protein condensates is about 10 mM, agreeing with experimental results. Furthermore, from a dynamic point of view, the effect of ATP on phase separation is also nonmonotonic. This work provides a clear physical description of the microscopic interaction and macroscopic phase diagram of the ATP-modulated phase separation.