Unifying coarse-grained force fields for folded and disordered proteins

Liquid–liquid phase separation drives the formation of biological condensates that play essential roles in transcriptional regulation and signal sensing. Computational modeling could provide high-resolution structural characterizations of these condensates and help uncover physicochemical interactions that dictate their stability. However, many protein molecules involved in phase separation often contain multiple ordered domains connected with flexible, structureless linkers. Simulating such proteins necessitates force fields with consistent accuracy for both folded and disordered proteins. We provide a critical review of existing coarse-grained force fields for disordered proteins and highlight the challenges in their application to folded proteins. After discussing existing algorithms for force field parameterization, we propose an optimization strategy that should lead to computer models with improved transferability across protein types.