Analytical Formulation and Field-Theoretic Simulation of Sequence-Specific Phase Separation of Proteinlike Heteropolymers with Short- and Long-Spatial-Range Interactions

Abstract

A theory for sequence dependent liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) in the study of biomolecular condensates is formulated by extending the random phase approximation (RPA) and field-theoretic simulation (FTS) of heteropolymers with spatially long-range Coulomb interactions to include the fundamental effects of short-range, hydrophobic-like interactions between amino acid residues. To this end, short-range effects are modeled by Yukawa interactions between multiple nonelectrostatic charges derived from an eigenvalue decomposition of pairwise residue-residue contact energies. Chain excluded volume is afforded by incompressibility constraints. A mean-field approximation leads to an effective Flory $\chi$ parameter, which, in conjunction with RPA, accounts for the contact-interaction effects of amino acid composition and the sequence-pattern effects of long-range electrostatics in IDP LLPS, whereas FTS based on the formulation provides full sequence dependence for both short- and long-range interactions. This general approach is illustrated here by applications to variants of a natural IDP in the context of several different amino-acid interaction schemes as well as a set of different model hydrophobic-polar sequences sharing the same composition. Effectiveness of the methodology is verified by coarse-grained explicit-chain molecular dynamics simulations.

arXiv comment54 pages, 13 figures, 168 references, with typographical errors in previous versions corrected and clarifications added. Accepted for publication in the Journal of Physical Chemistry B

References in corpus (24)

• Protein folding mediated by solvation: water expelling and formation of the hydrophobic core occurs after the structure collapse
• Comparative Roles of Charge, $\pi$ and Hydrophobic Interactions in Sequence-Dependent Phase Separation of Intrinsically Disordered Proteins
• Phase separation and single-chain compactness of charged disordered proteins are strongly correlated
• The Lennard-Jones potential: when (not) to use it
• Sequence-specific polyampholyte phase separation in membraneless organelles
• Nature of Driving Force for Protein Folding -- A Result From Analyzing the Statistical Potential
• Model for disordered proteins with strongly sequence-dependent liquid phase behavior
• Elastic ripening and inhibition of liquid-liquid phase separation
• Random-phase-approximation theory for sequence-dependent, biologically functional liquid-liquid phase separation of intrinsically disordered proteins
• Charge Pattern Matching as a "Fuzzy" Mode of Molecular Recognition for the Functional Phase Separations of Intrinsically Disordered Proteins
• Coarse-Grained Residue-Based Models of Disordered Protein Condensates: Utility and Limitations of Simple Charge Pattern Parameters
• A Lattice Model of Charge-Pattern-Dependent Polyampholyte Phase Separation
• A Modified Random Phase Approximation of Polyelectrolyte Solutions
• A unified analytical theory of heteropolymers for sequence-specific phase behaviors of polyelectrolytes and polyampholytes
• Analytical Theory for Sequence-Specific Binary Fuzzy Complexes of Charged Intrinsically Disordered Proteins
• A Simple Explicit-Solvent Model of Polyampholyte Phase Behaviors and its Ramifications for Dielectric Effects in Biomolecular Condensates
• Subcompartmentalization of polyampholyte species in organelle-like condensates is promoted by charge pattern mismatch and strong excluded-volume interaction
• Numerical Techniques for Applications of Analytical Theories to Sequence-Dependent Phase Separations of Intrinsically Disordered Proteins
• Small-Angle X-Ray Scattering Signatures of Conformational Heterogeneity and Homogeneity of Disordered Protein Ensembles
• Amino acid classes and the protein folding problem
• Diversity of phase transitions and phase separations in active fluids
• Finite-size scaling analysis of protein droplet formation
• Phase behavior of blocky charge lattice polymers: Crystals, liquids, sheets, filaments and clusters
• Field theory description of ion association in re-entrant phase separation of polyampholytes

Cited by in corpus (7)

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• Electrostatics of Salt-Dependent Reentrant Phase Behaviors Highlights Diverse Roles of ATP in Biomolecular Condensates
• Differential Effects of Sequence-Local versus Nonlocal Charge Patterns on Phase Separation and Conformational Dimensions of Polyampholytes as Model Intrinsically Disordered Proteins
• Intramolecular Structural Heterogeneity altered by Long-range Contacts in an Intrinsically Disordered Protein
• Emergence of multiphase condensates from a limited set of chemical building blocks
• Mesoscale properties of protein clusters determine the size and nature of liquid-liquid phase separation (LLPS)
• Programmable phase behavior in fluids with designable interactions