Role of Solvent Compatibility in the Phase Behavior of Binary Solutions of Weakly Associating Multivalent Polymers

Abstract

Condensate formation of biopolymer solutions, prominently those of various intrinsically disordered proteins (IDPs), is often driven by “sticky” interactions between associating residues, multivalently present along the polymer backbone. Using a ternary mean-field “stickers-and-spacers” model, we demonstrate that if sticker association is of the order of a few times the thermal energy, a delicate balance between specific binding and nonspecific polymer–solvent interactions gives rise to a particularly rich ternary phase behavior under physiological circumstances. For a generic system represented by a solution comprising multiassociative scaffold and client polymers, the difference in solvent compatibility between the polymers modulates the nature of isothermal liquid–liquid phase separation (LLPS) between associative and segregative. The calculations reveal regimes of dualistic phase behavior, where both types of LLPS occur within the same phase diagram, either associated with the presence of multiple miscibility gaps or a flip in the slope of the tie-lines belonging to a single coexistence region.

Promoter and Gene-Body RNA-Polymerase II co-exist in partial demixed condensates

“…The excellent fit with the simulated data, despite the fact that Flory-Huggins theory does not include a description for (long range) electrostatic interactions, supports considerable screening by the implicit background salt in the simulations, making the attractive forces between the polymers effectively short-ranged. Furthermore, owing to the predominance of a single type of interaction, a more complex mean-field model for fitting the data 69 would be redundant. The overall attraction between the polymers is captured by a negative polymer-polymer interaction parameter: χ AB = −2.36.…”

Role of Strong Localized vs Weak Distributed Interactions in Disordered Protein Phase Separation

“…Since our model sequences have the same degree of polymerization ( N = 20), their single-chain dimensions (i.e., at infinite dilution) are mainly dictated by the fraction of polar monomers X P and specific intramolecular interactions. Strong monomer attraction would lead to the collapse of the chain, mimicking poor solvent conditions, whereas pure repulsion would lead to chain expansion analogous to good solvent conditions. , Single-chain compactness has been shown to correlate with the propensity to phase separate both experimentally and computationally for a wide range of IDPs. − Here, we quantified single-chain compactness using the polymer’s radius of gyration R g , which we computed from the average of the trace of the gyration tensor. , To facilitate comparison of our sequence- and model-dependent results, we used a purely hydrophobic polymer ( X P = 0) with λ H = 1 and a purely hydrophilic polymer ( X P = 1) as reference sequences. For the purely hydrophobic polymer, the maximum monomer–monomer attraction was ∼0.3 k B T , so it behaved like a slightly attractive chain rather than a collapsed globule at infinite dilution, as demonstrated by the scaling exponent of 0.46 for the intrachain distance (Figure S2).…”

“…Strong monomer attraction would lead to the collapse of the chain, mimicking poor solvent conditions, whereas pure repulsion would lead to chain expansion analogous to good solvent conditions. 9 , 45 Single-chain compactness has been shown to correlate with the propensity to phase separate both experimentally and computationally for a wide range of IDPs. 46 − 48 Here, we quantified single-chain compactness using the polymer’s radius of gyration R g , which we computed from the average of the trace of the gyration tensor.…”

Theory and Simulation of Multiphase Coexistence in Biomolecular Mixtures

“…When the binding sites are assumed to represent individual amino acids of IDPs or short sequence motifs of IDPs and/or RNAs, associating fluid theory is commonly referred to as the “stickers-and-spacers” model of heteropolymer association. ,− In this case, a Flory–Huggins homopolymer model with a degree of polymerization much greater than the binding-site valence (i.e., the number of “stickers”) is typically taken as the reference model. Stickers-and-spacers applications of associating fluid theory have been successfully used to rationalize experimental observations of IDP-driven phase separation, including both thermodynamic and dynamical properties, in many contexts. ,, The assignment of the “stickers” to specific amino acids or short sequence motifs has varied depending on context across different studies, however, suggesting that additional contextual information may be required to predict the phase behavior of multicomponent IDP and RNA mixtures from their sequences.…”

“…When the binding sites are assumed to represent individual amino acids of IDPs or short sequence motifs of IDPs and/or RNAs, associating fluid theory is commonly referred to as the "stickers-and-spacers" model of heteropolymer association [4,[116][117][118]. In this case, a Flory-Huggins homopolymer model with a degree of polymerization much greater than the binding-site valence (i.e., the number of "stickers") is typically taken as the reference model.…”