Unifying coarse-grained force fields for folded and disordered proteins. (February 2022)

• Record Type: Journal Article
• Authors: Latham, Andrew P.; Zhang, Bin
• Is Part Of: Current opinion in structural biology. Volume 72(2022)
• Page Start: 63
• Page End: 70
• Publication Date: 2022-02
• Subjects: Coarse graining -- Force field parameterization -- Liquid–liquid phase separation -- Disordered proteins -- Protein folding; Molecular biology -- Periodicals; 570
• DOI: 10.1016/j.sbi.2021.08.006
• Languages: English
• ISSNs: 0959-440X

Abstract

Abstract: 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. Highlights: Many proteins involved in biological condensates consist of both folded and disordered domains. Existing coarse-grained force fields are often only applicable to either folded or disordered proteins, but not both. There is an urgent need to develop consistent protein force fields for studying liquid–liquid phase separation. Combining top-down and bottom-up force field parameterization schemes can lead to models transferable to both protein types.