Uncovering the molecular mechanism for dual effect of ATP on phase separation in FUS solution

TL;DR

This study elucidates how ATP modulates phase separation in FUS proteins through microscopic binding interactions and macroscopic phase behavior, revealing a non-monotonic, concentration-dependent effect consistent with experimental observations.

Contribution

The paper combines quantum mechanics, mean-field theory, and molecular simulations to uncover the molecular mechanism of ATP's dual effect on phase separation in FUS solutions.

Findings

ATP acts as a bivalent or trivalent binder.

Reentrant phase separation occurs depending on ATP concentration.

ATP dissolves protein condensates around 10 mM, matching experiments.

Abstract

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.