  Recent studies reported that adenosine triphosphate (ATP) could inhibit as
well as 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 indeed occurs
in dilute FUS solutions, resulting from the ATP-concentration--dependent
binding ability under different conditions. Importantly, 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 non-monotonic. This work provides a clear
physical description of the microscopic interaction and macroscopic phase
diagram of the ATP-modulated phase separation.
