Design of Protein Assemblies of Non-trivial Topology for Programmable Disassembly

• Applicant: Dr. Joanna Macnar
• Subject Area: Structural Biology ; Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 575199891

Protein nanocages have emerged as promising vehicles for drug delivery and biotechnology applications. While computational protein design has achieved remarkable success in creating stable assemblies - recognized by the 2024 Nobel Prize in Chemistry - methods for controlling assembly and disassembly dynamics remain limited. Here we propose to exploit non-trivial topological architectures, specifically Brunnian links, to engineer protein nanocages with unique "all-or-nothing" stability where disruption of any single component triggers complete disassembly. I will integrate state-of-the-art computational design methods with in vitro biophysical characterization to create protein-based Borromean rings with programmable disassembly properties. More specifically, I will tackle this challenge in three work packages to: (WP1) design structurally anisotropic protein rings that overcome the geometric constraints of Brunnian links; (WP2) engineer three-ring Borromean assemblies through symmetry-guided design; and (WP3) demonstrate controlled cargo release by incorporating stimulus-responsive elements in one ring that trigger complete cage disassembly. If successful, our approach will establish a new paradigm in protein engineering, enabling rational design of responsive biomaterials with unprecedented control over assembly dynamics. This work will advance fundamental understanding of topological protein assemblies while creating a new generation of materials for drug delivery, programmable biosensors, and biotechnology applications requiring precise spatiotemporal control.

• DFG Programme: WBP Position