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

TL;DR

This paper develops a comprehensive theoretical framework combining RPA and FTS to model sequence-specific phase separation in IDPs, incorporating both short-range hydrophobic and long-range electrostatic interactions, validated by molecular dynamics simulations.

Contribution

It introduces a novel field-theoretic approach that integrates short- and long-range interactions for sequence-dependent phase separation of heteropolymers.

Findings

Effective modeling of amino acid interactions in phase separation.

Validation of theory with molecular dynamics simulations.

Sequence-dependent LLPS behavior captured by the model.

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.