Charge-Pattern Dependent Sequestration of Globular Proteins in Membraneless Organelles

Condensation of polyampholytes into coacervates is driven by sequence-dependent charge correlations. It is proposed to be one of the mechanisms underlying the formation of membraneless organelles (MLOs) through liquid-liquid phase separation of intrinsically disordered proteins (IDPs), which are rich in charged residues and lack ordered structures. Unlike IDPs, globular proteins fold into complicated 3d structures and expose their charged residues to the surface to form specific surface charge patterns. We use coarse-grained molecular dynamics simulations to study the role of surface charge patterns in the sequestration of globular proteins in MLOs. In our coarse-grained model, globular proteins are modeled by spherical nanoparticles with patterned surface charges, while MLOs are represented by sequence-controlled polyampholyte coacervates. The free energy landscape of a globular protein partitioning between two MLOs is calculated by umbrella sampling. We have shown that the MLO formed by blocky polyampholytes prefers to uptake globular proteins with patchy surface charge, while the MLO formed by random polyampholytes shows a stronger affinity to globular proteins with random surface charge. Such "like dissolves like" behavior is consistent with the theoretical picture of the sequence/pattern-dependent electrostatic correlation.