De novo design of cytokine receptor binders from hetero-chiral building blocks

Advisor: Mohammad ElGamacy & Andrei Lupas

Location: University Hospital Tübingen & Max Planck Institute for Biology

We are looking for a PhD Student (m/f/d) to join our closely collaborating groups at the Max Planck Institute for Biology (Department of Protein Evolution) and the University Hospital Tübingen (Division of Translational Oncology – Department of Internal Medicine II).

Research project:
Design of functional proteins has so far relied on building proteins from the twenty canonical amino acids. Expanding this restricted vocabulary allows the design of proteins with novel structural and functional properties. For instance, synthetic amino acids can possess features such as size, polarity, acidity, solubility, or conformational distribution that depart from their canonical counterparts. Existing computational methods, however, are not suitable for designing synthetic proteins as they were built to learn patterns from sequences and structures of known proteins. This poses a challenge for designing proteins from non-natural building blocks, for which sequence and structure data are lacking. Through this interdisciplinary project, the doctoral candidate will combine computational and experimental techniques to specifically design heterochiral protein binders against different leukemia targets. The candidate will thus deploy bottom-up computational tools to design and simulate proteins that combine D- and L-amino acids. The candidate will combine biophysical measurements and cell-based assays to characterize the successful design candidates, and contrast their properties to existing leukemia-targeting proteins. The resulting heterochiral proteins are expected to comprise novel structural motifs, be hyper-resistant to proteolysis, and possess a low immunogenic footprint. This project thus establishes a new class of de novo-designed therapeutics, that hitherto has not been rationally designed.

The main stages of the project. The project will start by deriving force field parameters for selected non-canonical amino acids, and profiling their conformational tendencies through molecular dynamics simulations (left). These building blocks will then be incorporated into proteins designed to bind and antagonise leukemogenic receptors, which will be validated using biophysical and cell-based assays (right). — **The main stages of the project.** The project will start by deriving force field parameters for selected non-canonical amino acids, and profiling their conformational tendencies through molecular dynamics simulations (left). These building blocks will then be incorporated into proteins designed to bind and antagonise leukemogenic receptors, which will be validated using biophysical and cell-based assays (right).

**The main stages of the project.** The project will start by deriving force field parameters for selected non-canonical amino acids, and profiling their conformational tendencies through molecular dynamics simulations (left). These building blocks will then be incorporated into proteins designed to bind and antagonise leukemogenic receptors, which will be validated using biophysical and cell-based assays (right).

Overview of the project structure. The project will cover computational and experimental aspects. On the computational side, the work will involve parameter refinement, simulation of conformational tendencies, and full-fledged protein design using the Damietta software. On the experimental side, binding kinetics and specificity, on-cell binding and signaling blockade, and differential activity on leukemic and healthy blood progenitor cells will be assayed.

More information about the research of Andrei Lupas and a selection of recent publications can be found on his faculty page.

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Application deadline: 27 January 2025