Structural and Functional Synthetic Proteomimetics of Ankyrin Repeat Proteins

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With the insight that tandem repeat proteins evolved from more homogeneous ancestors,1–3 our central hypothesis is that their hallmark complex interaction surfaces can be emulated by simple synthetic repeating constructs. We ask two key questions in the proposed research: 1) Can higher order folding of simple, individual ankyrin repeats be induced by spatial organization on synthetic polymeric scaffolds allowing multivalency, and thus replicating such interaction surfaces? and 2) What is the simplest ankyrin repeat that can functionally recapitulate a high affinity PPI? To probe these questions, a polymer-based approach to proteomimetics will be employed. The proposed proteomimetic systems will provide insight into ankyrin repeat proteins by emulating the properties of proteins while remaining synthetically straightforward and structurally simple.4 Specifically, we propose protein-like polymers (PLPs)5–10 as these constructs are monodisperse, protein- sized macromolecules that are rapidly and scalably produced by polymerization of peptide-based monomers. The result is a peptide brush polymer wherein peptides are tethered to a hydrocarbon polymer backbone in a dense display. This results in a peptide topology that resembles repeat proteins, but where the peptides repeats are arranged on a synthetic scaffold.6,7 We hypothesize that this proteomimetic platform can enable conformational mimics of ankyrin repeat proteins, to serve as effective mimics for the disruption of PPIs as tools and therapeutics. The long-term goal of this application is the precise design of tandem repeat-mimetic PLPs for the formulation and delivery of therapeutic peptides and as chemical biology tools. With the combined knowledge from these lines of inquiry, reliable rules will be established for the creation of highly stable, yet effective PLPs that target protein-protein interactions in diseases. Furthermore, this knowledge will inform the design of proteomimetic materials for therapeutic applications more broadly. In addition to this research project, a training plan will be pursued to develop the expertise and proficiency of the candidate in soft matter synthesis and characterization, drawing upon the collaborative and motivated research environment in Prof. Gianneschi's group and the considerable resources available through Northwestern University. This plan will include honing skills in mentorship of students, presenting results, effective grant-writing, and the management of research groups. This training plan and research environment will help the candidate grow in their transition to new fields and lines of inquiry, towards the pursuit of an independent research career investigating bio-inspired materials for targeted drug delivery.