Understanding the assembly and dynamics of polymers formed by polar proteins

The control and regulation of self-assembly of proteins is important for many biological applications, such as protein purification, gene regulation, stress response and immune response. Recent experiments suggest that charge heterogeneity of proteins can be engineered to tune the liquid-liquid phase separation (LLPS) as well as often undesirable protein aggregations of both globular and disordered proteins. Understanding how charge heterogeneity affects protein self-assembly is key to developing strategies to regulate protein phase separation in a precise and programmable manner.

In this work, we develop a minimal model to elucidate how charge heterogeneity and excluded-volume effects together influence the self-assembly and dynamics of transient, physically bonded “polymers” formed by polar proteins.With a small set of effective tunable parameters—such as charge density, effective interaction angle, and excluded volume—we reproduce a wide range of topologies for protein-based macro-“polymers,” including chains, networks, and rings. Although the formation of physical “bonds” produces no byproducts, the resulting “polymerization” follows a condensation-like polymerization mechanism. Incorporating intrinsically disordered regions (IDRs) into the model shows that the excluded-volume effects of IDRs introduce geometrical frustration, resulting in a self-limiting self-assembly process. The simulation results agree well with recent experiments on “fiber” formation of yeast proteins by Nynke Hettema and Liedewij Lann.

Overall, our findings provide a promising framework for systematically understanding and controlling the self-assembly and phase separation of proteins with charge heterogeneity and IDRs.

We gratefully acknowledge insightful discussions with Nynke Hettema, Liedewij Laan, Kurt Kremer and Alexander Grosberg.