Coarse-grained residue-based models of disordered protein condensates: utility and limitations of simple charge pattern parameters

Abstract

Biomolecular condensates undergirded by phase separations of proteins and nucleic acids serve crucial biological functions. To gain physical insights into their genetic basis, we study how liquid-liquid phase separation (LLPS) of intrinsically disordered proteins (IDPs) depends on their sequence charge patterns using a continuum Langevin chain model wherein each amino acid residue is represented by a single bead. Charge patterns are characterized by the "blockiness" measure κ and the "sequence charge decoration" (SCD) parameter. Consistent with random phase approximation (RPA) theory and lattice simulations, LLPS propensity as characterized by critical temperature T * cr increases with increasingly negative SCD for a set of sequences showing a positive correlation between κ and −SCD. Relative to RPA, the simulated sequence-dependent variation in T * cr is often-though not alwayssmaller, whereas the simulated critical volume fractions are higher. However, for a set of sequences exhibiting an anti-correlation between κ and −SCD, the simulated T * cr 's are quite insensitive to either parameters. Additionally, we find that blocky sequences that allow for strong electrostatic repulsion can lead to coexistence curves with upward concavity as stipulated by RPA, but the LLPS propensity of a strictly alternating charge sequence was likely overestimated by RPA and lattice models because interchain stabilization of this sequence requires spatial alignments that are difficult to achieve in real space. These results help delineate the utility and limitations of the charge pattern parameters and of RPA, pointing to further efforts necessary for rationalizing the newly observed subtleties.

Thermodynamically driven assemblies and liquid–liquid phase separations in biology

“…They observed that IDPs with identical f + 's and f − 's can exhibit different conformations, depending on factors such as charge decoration, and post-translational modifications. The role of charge decoration on phase separation propensity has also been demonstrated in on-lattice MC [206] and coarse-grained MD [207] simulations. Note that it is nontrivial to account for such effects in sequence-based methods, demonstrating the importance of atomistic simulations in accessing the conformational ensemble of IDPs.…”

Temperature, Hydrostatic Pressure, and Osmolyte Effects on Liquid–Liquid Phase Separation in Protein Condensates: Physical Chemistry and Biological Implications

“…[129][130][131] In this context, progress has nonetheless been made in theoreticalp hysical understanding of how LLPS of IPDs might depend on their amino acid sequences by using coarse-grained approaches. These include analytical theory, [33,38,61,132,133] lattice [134] and continuum [9,135,136] residuebased explicit-chain models, [137] and field theory simulations. [138,139] These studies indicate that LLPS is sensitiven ot only to the net electric charge of an IDP buta lso the pattern of charged istribution along its sequence.…”

A unified analytical theory of heteropolymers for sequence-specific phase behaviors of polyelectrolytes and polyampholytes

“…This result suggests that inverse S-shaped phase boundaries can arise in general from a heterogeneous sequence charge pattern because it leads to the simultaneous presence of both attractive and repulsive interchain interactions (which can be counterion-mediated in the case of polyelectrolytes) and therefore allows for condensed-phase configurations with lower densities. 22 As a control, fG-RPA results are shown in Fig. 2(c).…”