Liquid-Liquid Phase Separation in a Minimal Explicit-Solvent Lattice Model Mimicking Protein Solutions

Abstract

Biomolecular condensates play essential roles in cellular processes, and recent efforts have focused on understanding their assembly and rational design principles. In this study, we have employed an explicit-solvent minimal statistical mechanical model based on the lattice-gas Hamiltonian with quenched disorder -- which mimics crowders -- to investigate how protein-solvent and protein-crowder interactions influence condensate phase behavior and morphology. The computed phase diagrams reveal rich behavior, including upper critical solution temperature (UCST), closed-loop, and reentrant type transitions under varying protein-solvent interactions at both equilibrium and out-of-equilibrium conditions. We elucidated the origin of these phase behavior changes and examined the role of protein-crowder interactions in modulating condensed phase morphology and stability. We further extended this model to binary protein mixtures where we studied the phase behavior in the presence and absence of quenched disorder. Without disorder, the system exhibits diverse phase-separated morphologies -- partially wetted, fully wetted, segregative, and associative -- with phase boundaries delicately sensitive protein-solvent interactions. The introduction of quenched disorder (or crowder) leads to a broader spectrum of complex morphologies, dictated by the interplay among protein-protein, protein-solvent, and protein-crowder interaction parameters. In general, this work underscores that protein-solvent and protein-crowder interactions, together with protein-protein interactions, can act as key regulatory parameters for modulating condensate morphology. These insights may guide future computational and experimental studies of liquid-liquid phase separation in biomolecular systems aimed at designing stimuli-responsive condensates.