Rational Design of Zwitterionic Polymers with Tunable Phase Separation Propensity

Zwitterionic polymers are emerging as promising candidates for forming fluid-like coacervates with desirable characteristics, including antifouling capabilities, stimulus responsiveness, and biocompatibility. These attributes make them particularly appealing for applications in the biomedical field, including bioseparation, biochemical analysis, and diagnostics. However, there are currently no clear guiding principles for predicting the phase separation behavior of zwitterionic polymers and informing the design of novel phase-separating polymers. In this study, we develop a workflow that combines molecular dynamics simulations, theory, and experiments to predict the phase separation propensity of zwitterionic polymers, as well as the material properties of the resulting coacervates. We validate our simulation-based workflow as a predictive tool by synthesizing new zwitterionic polymers that undergo no phase separation, liquid-liquid phase separation, or liquid-gel phase separation. Beyond their predictive power, we show that molecular simulations provide insights into the attractive homotypic intermolecular interactions mediated by distinct functional groups, rationalizing the large differences observed between zwitterionic monomers that exhibit minimal structural variations. Our approach provides valuable insights into the molecular principles governing the phase separation of distinct zwitterionic polymers, with important implications for the design of their materials.