Accurate model of liquid–liquid phase behavior of intrinsically disordered proteins from optimization of single-chain properties

2021/10/29 by Giulio Tesei, Thea K. Schulze, Ramón Crehuet +1 · 1 voice · 7 citations
Biochemistry, Genetics and Molecular Biology · #Lipid metabolism and biosynthesis #Protein Structure and Dynamics #RNA Research and Splicing

paper · doi:10.1073/pnas.2111696118

openalex publication_date 2021/10/29 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30

Abstract

Many intrinsically disordered proteins (IDPs) may undergo liquid-liquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalization of intracellular biochemical reactions. The phase behavior of IDPs is sequence dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intramolecular and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations, we show that the optimization of the intramolecular interactions results in improved predictions of protein self-association and LLPS.

Citations

• Mapping Long-Range Interactions in α-Synuclein using Spin-Label NMR and Ensemble Molecular Dynamics Simulations
• Experimental Parameterization of an Energy Function for the Simulation of Unfolded Proteins
• Valence and patterning of aromatic residues determine the phase behavior of prion-like domains
• Biomolecular Phase Separation: From Molecular Driving Forces to Macroscopic Properties
• OpenMM 7: Rapid development of high performance algorithms for molecular dynamics

Cited by

• Predicting Heteropolymer Interactions: Demixing and Hypermixing of Disordered Protein Sequences
• Design of intrinsically disordered protein variants with diverse structural properties
• Direct prediction of intrinsically disordered protein conformational properties from sequence
• Key processes required for the different stages of fungal carnivory by a nematode-trapping fungus
• Full‐Length FUS Protein Condensates Adopt a Domain‐Preferential Spatial Architecture
• Folded domains impose structural heterogeneity and attenuated dynamics in biomolecular condensates
• Backbone-mediated weakening of pairwise interactions enables percolation in peptide-based mimics of protein condensates

Discussions

• More recently, we applied this to data for a larger number of proteins for which we collected SAXS+NMR-PRE data from the literature to develop the CALVADOS simulation model that we benchmarked across [bsky, 2 points, 1 comments]

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