De novo design of small molecule-dependent protein assemblies to interface with biological systems

• Applicant: Professorin Dr. Alena Khmelinskaia
• Subject Area: Biochemistry ; Biophysics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 558049915

Protein design stands as a fundamental tool for the generation of novel protein materials, and can be invaluable for exploring protein structural and functional landscapes faster and more efficiently than natural evolution. Yet, programming proteins with controlled assembly processes remains an unsolved challenge, hindering their effective integration with biological systems. In contrast, natural proteins dynamically respond to environmental cues and can undergo changes in oligomeric states to transduce biochemical information, dynamically regulating cellular processes essential for life. Inspired by nature, we propose the de novo design of environmentally responsive protein assemblies based on small molecule binding. We will develop new computational protein design approaches (WP1) and combine them with state-of-the-art methods as well as in vitro biophysical characterization to interface protein-assemblies with lipid membranes by engineering: (i) oligomers dependent on membrane-bound metabolytes (WP2) and (ii) dynamic membrane-binding proteins (WP3). Ultimately, our approach will provide innovative methodologies to advance functional designability and utility of protein assemblies when interfacing with biological systems.

• DFG Programme: Research Grants