# Thermodynamic forces from protein and water govern condensate formation of an intrinsically disordered protein domain

## TL;DR

This study uses simulations to show how protein and water interactions drive the formation of biomolecular condensates in the FUS protein.

## Contribution

The study reveals the specific thermodynamic contributions of solvation entropy and protein interactions in condensate formation.

## Key findings

- Protein and water have comparable thermodynamic contributions to FUS condensate formation.
- Solvation entropy and protein interaction enthalpy are the most important driving forces.
- Released and retained water molecules counteract each other during condensate formation.

## Abstract

Liquid-liquid phase separation (LLPS) can drive a multitude of cellular processes by compartmentalizing biological cells via the formation of dense liquid biomolecular condensates, which can function as membraneless organelles. Despite its importance, the molecular-level understanding of the underlying thermodynamics of this process remains incomplete. In this study, we use atomistic molecular dynamics simulations of the low complexity domain (LCD) of human fused in sarcoma (FUS) protein to investigate the contributions of water and protein molecules to the free energy changes that govern LLPS. Both protein and water components are found to have comparably sizeable thermodynamic contributions to the formation of FUS condensates. Moreover, we quantify the counteracting effects of water molecules that are released into the bulk upon condensate formation and the waters retained within the protein droplets. Among the various factors considered, solvation entropy and protein interaction enthalpy are identified as the most important contributions, while solvation enthalpy and protein entropy changes are smaller. These results provide detailed molecular insights on the intricate thermodynamic interplay between protein- and solvation-related forces underlying the formation of biomolecular condensates.

In this work, the authors report atomistic molecular dynamics simulations showing that solvation entropy and protein-protein interactions are the main thermodynamic driving forces for the formation of condensates of the intrinsically disordered domain of the protein FUS.